WO2023192505A2 - Method for treating cancer with a dna damage repair enzyme inhibitor - Google Patents
Method for treating cancer with a dna damage repair enzyme inhibitor Download PDFInfo
- Publication number
- WO2023192505A2 WO2023192505A2 PCT/US2023/016940 US2023016940W WO2023192505A2 WO 2023192505 A2 WO2023192505 A2 WO 2023192505A2 US 2023016940 W US2023016940 W US 2023016940W WO 2023192505 A2 WO2023192505 A2 WO 2023192505A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cancer
- cell
- tumor
- inhibitor
- carcinoma
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 265
- 201000011510 cancer Diseases 0.000 title claims abstract description 250
- 238000000034 method Methods 0.000 title claims abstract description 166
- 230000005971 DNA damage repair Effects 0.000 title claims description 152
- 239000002532 enzyme inhibitor Substances 0.000 title abstract description 82
- 229940125532 enzyme inhibitor Drugs 0.000 title abstract description 79
- 230000007812 deficiency Effects 0.000 claims abstract description 35
- 108010076525 DNA Repair Enzymes Proteins 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 170
- 210000004027 cell Anatomy 0.000 claims description 81
- 239000003112 inhibitor Substances 0.000 claims description 81
- 239000003814 drug Substances 0.000 claims description 80
- 229940124597 therapeutic agent Drugs 0.000 claims description 74
- 102000004190 Enzymes Human genes 0.000 claims description 63
- 108090000790 Enzymes Proteins 0.000 claims description 63
- 229940088598 enzyme Drugs 0.000 claims description 63
- 229960000575 trastuzumab Drugs 0.000 claims description 59
- 238000011282 treatment Methods 0.000 claims description 57
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 50
- 229960000397 bevacizumab Drugs 0.000 claims description 49
- 229960003301 nivolumab Drugs 0.000 claims description 44
- 229960002621 pembrolizumab Drugs 0.000 claims description 44
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 43
- 108090000623 proteins and genes Proteins 0.000 claims description 42
- -1 BARE)] Proteins 0.000 claims description 38
- 230000002018 overexpression Effects 0.000 claims description 38
- 102100029764 DNA-directed DNA/RNA polymerase mu Human genes 0.000 claims description 37
- 206010060862 Prostate cancer Diseases 0.000 claims description 37
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 37
- 239000012472 biological sample Substances 0.000 claims description 37
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 37
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 36
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 36
- 229960005277 gemcitabine Drugs 0.000 claims description 36
- 229960000485 methotrexate Drugs 0.000 claims description 36
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 32
- 108010061914 DNA polymerase mu Proteins 0.000 claims description 31
- 229930012538 Paclitaxel Natural products 0.000 claims description 29
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 claims description 29
- 229960001592 paclitaxel Drugs 0.000 claims description 29
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 29
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 28
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 28
- RHXHGRAEPCAFML-UHFFFAOYSA-N 7-cyclopentyl-n,n-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=C2N(C3CCCC3)C(C(=O)N(C)C)=CC2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 RHXHGRAEPCAFML-UHFFFAOYSA-N 0.000 claims description 27
- 229950003687 ribociclib Drugs 0.000 claims description 27
- 230000006870 function Effects 0.000 claims description 25
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 24
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 claims description 24
- 239000012453 solvate Substances 0.000 claims description 24
- 206010006187 Breast cancer Diseases 0.000 claims description 23
- 208000026310 Breast neoplasm Diseases 0.000 claims description 23
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical group C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 23
- 229960005395 cetuximab Drugs 0.000 claims description 23
- 229960005420 etoposide Drugs 0.000 claims description 23
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims description 23
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 claims description 22
- 101100388059 Drosophila melanogaster PolQ gene Proteins 0.000 claims description 22
- 229960004117 capecitabine Drugs 0.000 claims description 22
- 239000003795 chemical substances by application Substances 0.000 claims description 22
- 229960003668 docetaxel Drugs 0.000 claims description 22
- 229960004768 irinotecan Drugs 0.000 claims description 22
- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-CFWMRBGOSA-N 0.000 claims description 22
- VVIAGPKUTFNRDU-STQMWFEESA-N (6S)-5-formyltetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1C=O)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-STQMWFEESA-N 0.000 claims description 21
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 21
- 229960002949 fluorouracil Drugs 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 20
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 19
- 201000010536 head and neck cancer Diseases 0.000 claims description 19
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 19
- 206010009944 Colon cancer Diseases 0.000 claims description 18
- 206010033128 Ovarian cancer Diseases 0.000 claims description 18
- HWGQMRYQVZSGDQ-HZPDHXFCSA-N chembl3137320 Chemical compound CN1N=CN=C1[C@H]([C@H](N1)C=2C=CC(F)=CC=2)C2=NNC(=O)C3=C2C1=CC(F)=C3 HWGQMRYQVZSGDQ-HZPDHXFCSA-N 0.000 claims description 18
- FDLYAMZZIXQODN-UHFFFAOYSA-N olaparib Chemical group FC1=CC=C(CC=2C3=CC=CC=C3C(=O)NN=2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FDLYAMZZIXQODN-UHFFFAOYSA-N 0.000 claims description 18
- 102000036365 BRCA1 Human genes 0.000 claims description 17
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 17
- 229960004397 cyclophosphamide Drugs 0.000 claims description 17
- 201000005202 lung cancer Diseases 0.000 claims description 17
- 208000020816 lung neoplasm Diseases 0.000 claims description 17
- 108700010154 BRCA2 Genes Proteins 0.000 claims description 16
- 108010069236 Goserelin Proteins 0.000 claims description 16
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims description 16
- 229960003852 atezolizumab Drugs 0.000 claims description 16
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims description 16
- 230000006801 homologous recombination Effects 0.000 claims description 16
- 238000002744 homologous recombination Methods 0.000 claims description 16
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 claims description 15
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 claims description 15
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 claims description 15
- 239000005551 L01XE03 - Erlotinib Substances 0.000 claims description 15
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 claims description 15
- 208000029742 colonic neoplasm Diseases 0.000 claims description 15
- 229960005167 everolimus Drugs 0.000 claims description 15
- 229960003881 letrozole Drugs 0.000 claims description 15
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 15
- 229960003048 vinblastine Drugs 0.000 claims description 15
- STUWGJZDJHPWGZ-LBPRGKRZSA-N (2S)-N1-[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)-4-pyridinyl]-2-thiazolyl]pyrrolidine-1,2-dicarboxamide Chemical compound S1C(C=2C=C(N=CC=2)C(C)(C)C(F)(F)F)=C(C)N=C1NC(=O)N1CCC[C@H]1C(N)=O STUWGJZDJHPWGZ-LBPRGKRZSA-N 0.000 claims description 14
- AOMXMOCNKJTRQP-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound C1=CC(NC(=O)NOC)=CC=C1C1=C(CN(C)C)C(C(=O)N(C=2N=NC(OC)=CC=2)C(=O)N2CC=3C(=CC=CC=3F)F)=C2S1 AOMXMOCNKJTRQP-UHFFFAOYSA-N 0.000 claims description 14
- PLIXOHWIPDGJEI-OJSHLMAWSA-N 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]-1h-pyrimidine-2,4-dione;1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-(trifluoromethyl)pyrimidine-2,4-dione;hydrochloride Chemical compound Cl.N1C(=O)NC(=O)C(Cl)=C1CN1C(=N)CCC1.C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 PLIXOHWIPDGJEI-OJSHLMAWSA-N 0.000 claims description 14
- 108010037003 Buserelin Proteins 0.000 claims description 14
- 239000002147 L01XE04 - Sunitinib Substances 0.000 claims description 14
- 239000002136 L01XE07 - Lapatinib Substances 0.000 claims description 14
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 claims description 14
- 108010050144 Triptorelin Pamoate Proteins 0.000 claims description 14
- 229950001573 abemaciclib Drugs 0.000 claims description 14
- 229940028652 abraxane Drugs 0.000 claims description 14
- 108010052004 acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide Proteins 0.000 claims description 14
- 108010081667 aflibercept Proteins 0.000 claims description 14
- HJBWBFZLDZWPHF-UHFFFAOYSA-N apalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C2(CCC2)C(=O)N(C=2C=C(C(C#N)=NC=2)C(F)(F)F)C1=S HJBWBFZLDZWPHF-UHFFFAOYSA-N 0.000 claims description 14
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical group CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 claims description 14
- MEUCPCLKGZSHTA-XYAYPHGZSA-N degarelix Chemical compound C([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CC=1C=CC(NC(=O)[C@H]2NC(=O)NC(=O)C2)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(NC(N)=O)C=C1 MEUCPCLKGZSHTA-XYAYPHGZSA-N 0.000 claims description 14
- UFNVPOGXISZXJD-JBQZKEIOSA-N eribulin Chemical compound C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 UFNVPOGXISZXJD-JBQZKEIOSA-N 0.000 claims description 14
- 229940087476 femara Drugs 0.000 claims description 14
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical group C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 claims description 14
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 claims description 14
- OKKDEIYWILRZIA-OSZBKLCCSA-N gemcitabine hydrochloride Chemical compound [H+].[Cl-].O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 OKKDEIYWILRZIA-OSZBKLCCSA-N 0.000 claims description 14
- 229940020967 gemzar Drugs 0.000 claims description 14
- 229940022353 herceptin Drugs 0.000 claims description 14
- FABUFPQFXZVHFB-PVYNADRNSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-PVYNADRNSA-N 0.000 claims description 14
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 claims description 14
- 229960004338 leuprorelin Drugs 0.000 claims description 14
- 229940008678 levoleucovorin Drugs 0.000 claims description 14
- CMJCXYNUCSMDBY-ZDUSSCGKSA-N lgx818 Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 CMJCXYNUCSMDBY-ZDUSSCGKSA-N 0.000 claims description 14
- 229960004857 mitomycin Drugs 0.000 claims description 14
- UZWDCWONPYILKI-UHFFFAOYSA-N n-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-amine Chemical compound C1CN(CC)CCN1CC(C=N1)=CC=C1NC1=NC=C(F)C(C=2C=C3N(C(C)C)C(C)=NC3=C(F)C=2)=N1 UZWDCWONPYILKI-UHFFFAOYSA-N 0.000 claims description 14
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 claims description 14
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 claims description 14
- 229960001972 panitumumab Drugs 0.000 claims description 14
- 229960002633 ramucirumab Drugs 0.000 claims description 14
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 claims description 14
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 claims description 14
- 229940063683 taxotere Drugs 0.000 claims description 14
- 229940066453 tecentriq Drugs 0.000 claims description 14
- 229960001196 thiotepa Drugs 0.000 claims description 14
- 229940111528 trexall Drugs 0.000 claims description 14
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 claims description 14
- 229940053867 xeloda Drugs 0.000 claims description 14
- 108700020463 BRCA1 Proteins 0.000 claims description 13
- 101150072950 BRCA1 gene Proteins 0.000 claims description 13
- 108010050904 Interferons Proteins 0.000 claims description 13
- 102000014150 Interferons Human genes 0.000 claims description 13
- 229940120638 avastin Drugs 0.000 claims description 13
- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 claims description 13
- HHXHVIJIIXKSOE-QILQGKCVSA-N histrelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC(N=C1)=CN1CC1=CC=CC=C1 HHXHVIJIIXKSOE-QILQGKCVSA-N 0.000 claims description 13
- 229940079322 interferon Drugs 0.000 claims description 13
- KLEAIHJJLUAXIQ-JDRGBKBRSA-N irinotecan hydrochloride hydrate Chemical compound O.O.O.Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 KLEAIHJJLUAXIQ-JDRGBKBRSA-N 0.000 claims description 13
- 229960002087 pertuzumab Drugs 0.000 claims description 13
- 229940049679 trastuzumab deruxtecan Drugs 0.000 claims description 13
- 229960000572 olaparib Drugs 0.000 claims description 11
- 229950004550 talazoparib Drugs 0.000 claims description 11
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 claims description 10
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 claims description 10
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 claims description 10
- 229940044665 STING agonist Drugs 0.000 claims description 9
- UVIQSJCZCSLXRZ-UBUQANBQSA-N abiraterone acetate Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](CC4=CC[C@H]31)OC(=O)C)C=C2C1=CC=CN=C1 UVIQSJCZCSLXRZ-UBUQANBQSA-N 0.000 claims description 9
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 9
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 9
- 229960004316 cisplatin Drugs 0.000 claims description 9
- 229960001433 erlotinib Drugs 0.000 claims description 9
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 claims description 8
- 108700020462 BRCA2 Proteins 0.000 claims description 8
- 102000052609 BRCA2 Human genes 0.000 claims description 8
- 101150008921 Brca2 gene Proteins 0.000 claims description 8
- 229940009456 adriamycin Drugs 0.000 claims description 8
- 229960002932 anastrozole Drugs 0.000 claims description 8
- 229960000997 bicalutamide Drugs 0.000 claims description 8
- 229960004562 carboplatin Drugs 0.000 claims description 8
- 229960004679 doxorubicin Drugs 0.000 claims description 8
- 229950009791 durvalumab Drugs 0.000 claims description 8
- 229960000255 exemestane Drugs 0.000 claims description 8
- 229960002258 fulvestrant Drugs 0.000 claims description 8
- 229960002913 goserelin Drugs 0.000 claims description 8
- 230000005764 inhibitory process Effects 0.000 claims description 8
- 229960001756 oxaliplatin Drugs 0.000 claims description 8
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 8
- 229960005079 pemetrexed Drugs 0.000 claims description 8
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 claims description 8
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 claims description 8
- 229960001603 tamoxifen Drugs 0.000 claims description 8
- 229960000303 topotecan Drugs 0.000 claims description 8
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 claims description 8
- 229960002066 vinorelbine Drugs 0.000 claims description 8
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 7
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 claims description 7
- 102100033195 DNA ligase 4 Human genes 0.000 claims description 7
- 102100029094 DNA repair endonuclease XPF Human genes 0.000 claims description 7
- 101000702606 Homo sapiens Structure-specific endonuclease subunit SLX4 Proteins 0.000 claims description 7
- 108010005714 Interferon beta-1b Proteins 0.000 claims description 7
- 239000002138 L01XE21 - Regorafenib Substances 0.000 claims description 7
- 108010000817 Leuprolide Proteins 0.000 claims description 7
- 229930192392 Mitomycin Natural products 0.000 claims description 7
- LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 claims description 7
- 229940126227 Orgovyx Drugs 0.000 claims description 7
- 108010019160 Pancreatin Proteins 0.000 claims description 7
- 102100031003 Structure-specific endonuclease subunit SLX4 Human genes 0.000 claims description 7
- 229940124653 Talzenna Drugs 0.000 claims description 7
- IWEQQRMGNVVKQW-OQKDUQJOSA-N Toremifene citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 IWEQQRMGNVVKQW-OQKDUQJOSA-N 0.000 claims description 7
- 229940064305 adrucil Drugs 0.000 claims description 7
- 229950010482 alpelisib Drugs 0.000 claims description 7
- 229940004511 androxy Drugs 0.000 claims description 7
- 229950007511 apalutamide Drugs 0.000 claims description 7
- 229940078010 arimidex Drugs 0.000 claims description 7
- 229940087620 aromasin Drugs 0.000 claims description 7
- 229940021459 betaseron Drugs 0.000 claims description 7
- 229940124659 braftovi Drugs 0.000 claims description 7
- 229960002719 buserelin Drugs 0.000 claims description 7
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 claims description 7
- KVUAALJSMIVURS-QNTKWALQSA-L calcium;(2s)-2-[[4-[[(6s)-2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl]methylamino]benzoyl]amino]pentanedioate Chemical compound [Ca+2].C([C@@H]1N(C=O)C=2C(=O)N=C(NC=2NC1)N)NC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-QNTKWALQSA-L 0.000 claims description 7
- 229940088954 camptosar Drugs 0.000 claims description 7
- 229940097647 casodex Drugs 0.000 claims description 7
- 229960002272 degarelix Drugs 0.000 claims description 7
- 229950001969 encorafenib Drugs 0.000 claims description 7
- 229940082789 erbitux Drugs 0.000 claims description 7
- 229960003649 eribulin Drugs 0.000 claims description 7
- 229940011871 estrogen Drugs 0.000 claims description 7
- 239000000262 estrogen Substances 0.000 claims description 7
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical group COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 claims description 7
- 229960000752 etoposide phosphate Drugs 0.000 claims description 7
- 229940043168 fareston Drugs 0.000 claims description 7
- 229940087861 faslodex Drugs 0.000 claims description 7
- 229940002006 firmagon Drugs 0.000 claims description 7
- 229960001751 fluoxymesterone Drugs 0.000 claims description 7
- 229960002074 flutamide Drugs 0.000 claims description 7
- 235000008191 folinic acid Nutrition 0.000 claims description 7
- 239000011672 folinic acid Substances 0.000 claims description 7
- 229940011343 fusilev Drugs 0.000 claims description 7
- 229940118951 halaven Drugs 0.000 claims description 7
- 229960002193 histrelin Drugs 0.000 claims description 7
- 108700020746 histrelin Proteins 0.000 claims description 7
- 229940088013 hycamtin Drugs 0.000 claims description 7
- 229940061301 ibrance Drugs 0.000 claims description 7
- 229960002014 ixabepilone Drugs 0.000 claims description 7
- 229940111707 ixempra Drugs 0.000 claims description 7
- 229960004891 lapatinib Drugs 0.000 claims description 7
- 229960001691 leucovorin Drugs 0.000 claims description 7
- 208000032839 leukemia Diseases 0.000 claims description 7
- 229940024740 lonsurf Drugs 0.000 claims description 7
- 108010078259 luprolide acetate gel depot Proteins 0.000 claims description 7
- 229940100352 lynparza Drugs 0.000 claims description 7
- 229940101513 menest Drugs 0.000 claims description 7
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 claims description 7
- 229940099637 nilandron Drugs 0.000 claims description 7
- 229960002653 nilutamide Drugs 0.000 claims description 7
- 229940048191 onivyde Drugs 0.000 claims description 7
- 229960004390 palbociclib Drugs 0.000 claims description 7
- 229940055695 pancreatin Drugs 0.000 claims description 7
- 229940124654 piqray Drugs 0.000 claims description 7
- 229960004836 regorafenib Drugs 0.000 claims description 7
- 229950004238 relugolix Drugs 0.000 claims description 7
- 229950001460 sacituzumab Drugs 0.000 claims description 7
- 229950000143 sacituzumab govitecan Drugs 0.000 claims description 7
- ULRUOUDIQPERIJ-PQURJYPBSA-N sacituzumab govitecan Chemical compound N([C@@H](CCCCN)C(=O)NC1=CC=C(C=C1)COC(=O)O[C@]1(CC)C(=O)OCC2=C1C=C1N(C2=O)CC2=C(C3=CC(O)=CC=C3N=C21)CC)C(=O)COCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCN(N=N1)C=C1CNC(=O)C(CC1)CCC1CN1C(=O)CC(SC[C@H](N)C(O)=O)C1=O ULRUOUDIQPERIJ-PQURJYPBSA-N 0.000 claims description 7
- 229940034810 soltamox Drugs 0.000 claims description 7
- 229940090374 stivarga Drugs 0.000 claims description 7
- 229960001052 streptozocin Drugs 0.000 claims description 7
- 229960001796 sunitinib Drugs 0.000 claims description 7
- 229940034785 sutent Drugs 0.000 claims description 7
- 229940120982 tarceva Drugs 0.000 claims description 7
- RCINICONZNJXQF-XAZOAEDWSA-N taxol® Chemical compound O([C@@H]1[C@@]2(CC(C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3(C21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-XAZOAEDWSA-N 0.000 claims description 7
- 229940024726 tipiracil / trifluridine Drugs 0.000 claims description 7
- 229940035307 toposar Drugs 0.000 claims description 7
- 229960005026 toremifene Drugs 0.000 claims description 7
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 claims description 7
- 229960001612 trastuzumab emtansine Drugs 0.000 claims description 7
- 229940032510 trelstar Drugs 0.000 claims description 7
- 229960004824 triptorelin Drugs 0.000 claims description 7
- 229940094060 tykerb Drugs 0.000 claims description 7
- 229940085728 xtandi Drugs 0.000 claims description 7
- 229940055760 yervoy Drugs 0.000 claims description 7
- 229940036061 zaltrap Drugs 0.000 claims description 7
- 229940053890 zanosar Drugs 0.000 claims description 7
- 229960002760 ziv-aflibercept Drugs 0.000 claims description 7
- 229940033942 zoladex Drugs 0.000 claims description 7
- 229940051084 zytiga Drugs 0.000 claims description 7
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 6
- 108010003272 Hyaluronate lyase Proteins 0.000 claims description 6
- 102000001974 Hyaluronidases Human genes 0.000 claims description 6
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 6
- 239000012661 PARP inhibitor Substances 0.000 claims description 6
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 claims description 6
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 6
- 229960004671 enzalutamide Drugs 0.000 claims description 6
- 229960002773 hyaluronidase Drugs 0.000 claims description 6
- 230000004797 therapeutic response Effects 0.000 claims description 6
- 229940097704 vantas Drugs 0.000 claims description 6
- 239000012827 ATM inhibitor Substances 0.000 claims description 5
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 claims description 5
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 claims description 5
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 5
- 229940120655 eloxatin Drugs 0.000 claims description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 5
- 102100035631 Bloom syndrome protein Human genes 0.000 claims description 4
- 102100040484 Claspin Human genes 0.000 claims description 4
- 101710117926 Claspin Proteins 0.000 claims description 4
- 102100038111 Cyclin-dependent kinase 12 Human genes 0.000 claims description 4
- 102100029995 DNA ligase 1 Human genes 0.000 claims description 4
- 102100039116 DNA repair protein RAD50 Human genes 0.000 claims description 4
- 102100034484 DNA repair protein RAD51 homolog 3 Human genes 0.000 claims description 4
- 102100034546 E3 ubiquitin-protein ligase FANCL Human genes 0.000 claims description 4
- 108010087740 Fanconi Anemia Complementation Group A protein Proteins 0.000 claims description 4
- 102000009095 Fanconi Anemia Complementation Group A protein Human genes 0.000 claims description 4
- 108010027673 Fanconi Anemia Complementation Group C protein Proteins 0.000 claims description 4
- 108010026653 Fanconi Anemia Complementation Group D2 protein Proteins 0.000 claims description 4
- 102000013601 Fanconi Anemia Complementation Group D2 protein Human genes 0.000 claims description 4
- 108010077898 Fanconi Anemia Complementation Group E protein Proteins 0.000 claims description 4
- 102000010634 Fanconi Anemia Complementation Group E protein Human genes 0.000 claims description 4
- 108010022012 Fanconi Anemia Complementation Group F protein Proteins 0.000 claims description 4
- 102000012216 Fanconi Anemia Complementation Group F protein Human genes 0.000 claims description 4
- 108010033305 Fanconi Anemia Complementation Group G protein Proteins 0.000 claims description 4
- 102000007122 Fanconi Anemia Complementation Group G protein Human genes 0.000 claims description 4
- 108700026162 Fanconi Anemia Complementation Group L protein Proteins 0.000 claims description 4
- 108010067741 Fanconi Anemia Complementation Group N protein Proteins 0.000 claims description 4
- 102000016627 Fanconi Anemia Complementation Group N protein Human genes 0.000 claims description 4
- 102100034552 Fanconi anemia group M protein Human genes 0.000 claims description 4
- 101000884345 Homo sapiens Cyclin-dependent kinase 12 Proteins 0.000 claims description 4
- 101000863770 Homo sapiens DNA ligase 1 Proteins 0.000 claims description 4
- 101000743929 Homo sapiens DNA repair protein RAD50 Proteins 0.000 claims description 4
- 101001132271 Homo sapiens DNA repair protein RAD51 homolog 3 Proteins 0.000 claims description 4
- 101000914679 Homo sapiens Fanconi anemia group B protein Proteins 0.000 claims description 4
- 101000848174 Homo sapiens Fanconi anemia group I protein Proteins 0.000 claims description 4
- 101000848187 Homo sapiens Fanconi anemia group M protein Proteins 0.000 claims description 4
- 101000702559 Homo sapiens Probable global transcription activator SNF2L2 Proteins 0.000 claims description 4
- 102100031021 Probable global transcription activator SNF2L2 Human genes 0.000 claims description 4
- 229950011068 niraparib Drugs 0.000 claims description 4
- PCHKPVIQAHNQLW-CQSZACIVSA-N niraparib Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1[C@@H]1CCCNC1 PCHKPVIQAHNQLW-CQSZACIVSA-N 0.000 claims description 4
- 229950004707 rucaparib Drugs 0.000 claims description 4
- HMABYWSNWIZPAG-UHFFFAOYSA-N rucaparib Chemical compound C1=CC(CNC)=CC=C1C(N1)=C2CCNC(=O)C3=C2C1=CC(F)=C3 HMABYWSNWIZPAG-UHFFFAOYSA-N 0.000 claims description 4
- 108010073629 xeroderma pigmentosum group F protein Proteins 0.000 claims description 4
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 3
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 3
- 206010000871 Acute monocytic leukaemia Diseases 0.000 claims description 3
- 208000011691 Burkitt lymphomas Diseases 0.000 claims description 3
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 3
- 208000032612 Glial tumor Diseases 0.000 claims description 3
- 206010018338 Glioma Diseases 0.000 claims description 3
- 208000002250 Hematologic Neoplasms Diseases 0.000 claims description 3
- 101000729474 Homo sapiens DNA-directed RNA polymerase I subunit RPA1 Proteins 0.000 claims description 3
- 101001092125 Homo sapiens Replication protein A 70 kDa DNA-binding subunit Proteins 0.000 claims description 3
- 208000035489 Monocytic Acute Leukemia Diseases 0.000 claims description 3
- 208000034578 Multiple myelomas Diseases 0.000 claims description 3
- 206010029260 Neuroblastoma Diseases 0.000 claims description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 3
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 3
- 102100035729 Replication protein A 70 kDa DNA-binding subunit Human genes 0.000 claims description 3
- 206010039491 Sarcoma Diseases 0.000 claims description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 3
- 201000010881 cervical cancer Diseases 0.000 claims description 3
- 201000004101 esophageal cancer Diseases 0.000 claims description 3
- 230000002349 favourable effect Effects 0.000 claims description 3
- 231100000518 lethal Toxicity 0.000 claims description 3
- 230000001665 lethal effect Effects 0.000 claims description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 3
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 206010033701 Papillary thyroid cancer Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 2
- 229960004103 abiraterone acetate Drugs 0.000 claims description 2
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 201000005962 mycosis fungoides Diseases 0.000 claims 3
- 206010044412 transitional cell carcinoma Diseases 0.000 claims 3
- 208000036170 B-Cell Marginal Zone Lymphoma Diseases 0.000 claims 2
- 201000009030 Carcinoma Diseases 0.000 claims 2
- 206010025323 Lymphomas Diseases 0.000 claims 2
- 208000007913 Pituitary Neoplasms Diseases 0.000 claims 2
- 208000002669 Sex Cord-Gonadal Stromal Tumors Diseases 0.000 claims 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims 2
- 208000009956 adenocarcinoma Diseases 0.000 claims 2
- 206010016629 fibroma Diseases 0.000 claims 2
- 206010017758 gastric cancer Diseases 0.000 claims 2
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 claims 2
- 201000001441 melanoma Diseases 0.000 claims 2
- 206010041823 squamous cell carcinoma Diseases 0.000 claims 2
- 201000011549 stomach cancer Diseases 0.000 claims 2
- 208000023747 urothelial carcinoma Diseases 0.000 claims 2
- 208000002008 AIDS-Related Lymphoma Diseases 0.000 claims 1
- 208000007876 Acrospiroma Diseases 0.000 claims 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 claims 1
- 208000003200 Adenoma Diseases 0.000 claims 1
- 206010001233 Adenoma benign Diseases 0.000 claims 1
- 208000001794 Adipose Tissue Neoplasms Diseases 0.000 claims 1
- 208000016683 Adult T-cell leukemia/lymphoma Diseases 0.000 claims 1
- 208000037540 Alveolar soft tissue sarcoma Diseases 0.000 claims 1
- 208000001446 Anaplastic Thyroid Carcinoma Diseases 0.000 claims 1
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 claims 1
- 206010002240 Anaplastic thyroid cancer Diseases 0.000 claims 1
- 206010051810 Angiomyolipoma Diseases 0.000 claims 1
- 201000003076 Angiosarcoma Diseases 0.000 claims 1
- 206010003571 Astrocytoma Diseases 0.000 claims 1
- 201000008271 Atypical teratoid rhabdoid tumor Diseases 0.000 claims 1
- 208000003950 B-cell lymphoma Diseases 0.000 claims 1
- 208000032568 B-cell prolymphocytic leukaemia Diseases 0.000 claims 1
- 206010004146 Basal cell carcinoma Diseases 0.000 claims 1
- 206010004453 Benign salivary gland neoplasm Diseases 0.000 claims 1
- 206010005949 Bone cancer Diseases 0.000 claims 1
- 208000018084 Bone neoplasm Diseases 0.000 claims 1
- 208000003174 Brain Neoplasms Diseases 0.000 claims 1
- 208000007690 Brenner tumor Diseases 0.000 claims 1
- 206010073258 Brenner tumour Diseases 0.000 claims 1
- 206010070487 Brown tumour Diseases 0.000 claims 1
- 208000009458 Carcinoma in Situ Diseases 0.000 claims 1
- 201000000274 Carcinosarcoma Diseases 0.000 claims 1
- 208000007389 Cementoma Diseases 0.000 claims 1
- 206010007953 Central nervous system lymphoma Diseases 0.000 claims 1
- 206010008583 Chloroma Diseases 0.000 claims 1
- 201000005262 Chondroma Diseases 0.000 claims 1
- 201000009047 Chordoma Diseases 0.000 claims 1
- 208000006332 Choriocarcinoma Diseases 0.000 claims 1
- 208000004378 Choroid plexus papilloma Diseases 0.000 claims 1
- 206010009253 Clear cell sarcoma of the kidney Diseases 0.000 claims 1
- 208000009798 Craniopharyngioma Diseases 0.000 claims 1
- 208000008334 Dermatofibrosarcoma Diseases 0.000 claims 1
- 208000008743 Desmoplastic Small Round Cell Tumor Diseases 0.000 claims 1
- 206010064581 Desmoplastic small round cell tumour Diseases 0.000 claims 1
- 208000007033 Dysgerminoma Diseases 0.000 claims 1
- 201000009051 Embryonal Carcinoma Diseases 0.000 claims 1
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 claims 1
- 208000002460 Enteropathy-Associated T-Cell Lymphoma Diseases 0.000 claims 1
- 208000033832 Eosinophilic Acute Leukemia Diseases 0.000 claims 1
- 208000036566 Erythroleukaemia Diseases 0.000 claims 1
- 206010061850 Extranodal marginal zone B-cell lymphoma (MALT type) Diseases 0.000 claims 1
- 201000008808 Fibrosarcoma Diseases 0.000 claims 1
- 206010016935 Follicular thyroid cancer Diseases 0.000 claims 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims 1
- 208000021309 Germ cell tumor Diseases 0.000 claims 1
- 201000005409 Gliomatosis cerebri Diseases 0.000 claims 1
- 206010068601 Glioneuronal tumour Diseases 0.000 claims 1
- 206010018404 Glucagonoma Diseases 0.000 claims 1
- 208000005234 Granulosa Cell Tumor Diseases 0.000 claims 1
- 208000035773 Gynandroblastoma Diseases 0.000 claims 1
- 206010066476 Haematological malignancy Diseases 0.000 claims 1
- 208000006050 Hemangiopericytoma Diseases 0.000 claims 1
- 208000001258 Hemangiosarcoma Diseases 0.000 claims 1
- 208000017604 Hodgkin disease Diseases 0.000 claims 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 claims 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims 1
- 208000029966 Hutchinson Melanotic Freckle Diseases 0.000 claims 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 claims 1
- 208000008839 Kidney Neoplasms Diseases 0.000 claims 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims 1
- 208000006404 Large Granular Lymphocytic Leukemia Diseases 0.000 claims 1
- 208000032004 Large-Cell Anaplastic Lymphoma Diseases 0.000 claims 1
- 206010023825 Laryngeal cancer Diseases 0.000 claims 1
- 206010024218 Lentigo maligna Diseases 0.000 claims 1
- 201000004462 Leydig Cell Tumor Diseases 0.000 claims 1
- 206010025219 Lymphangioma Diseases 0.000 claims 1
- 206010025312 Lymphoma AIDS related Diseases 0.000 claims 1
- 201000003791 MALT lymphoma Diseases 0.000 claims 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 claims 1
- 206010064281 Malignant atrophic papulosis Diseases 0.000 claims 1
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims 1
- 208000009018 Medullary thyroid cancer Diseases 0.000 claims 1
- 208000000172 Medulloblastoma Diseases 0.000 claims 1
- 208000035490 Megakaryoblastic Acute Leukemia Diseases 0.000 claims 1
- 208000002030 Merkel cell carcinoma Diseases 0.000 claims 1
- 206010027406 Mesothelioma Diseases 0.000 claims 1
- 208000003445 Mouth Neoplasms Diseases 0.000 claims 1
- 208000007727 Muscle Tissue Neoplasms Diseases 0.000 claims 1
- 206010073137 Myxoid liposarcoma Diseases 0.000 claims 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 claims 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims 1
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 claims 1
- 201000004404 Neurofibroma Diseases 0.000 claims 1
- 208000005890 Neuroma Diseases 0.000 claims 1
- 206010029488 Nodular melanoma Diseases 0.000 claims 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims 1
- 206010061872 Non-renal cell carcinoma of kidney Diseases 0.000 claims 1
- 201000010133 Oligodendroglioma Diseases 0.000 claims 1
- 206010048757 Oncocytoma Diseases 0.000 claims 1
- 206010073261 Ovarian theca cell tumour Diseases 0.000 claims 1
- 208000002063 Oxyphilic Adenoma Diseases 0.000 claims 1
- 201000010630 Pancoast tumor Diseases 0.000 claims 1
- 208000015330 Pancoast tumour Diseases 0.000 claims 1
- 208000037064 Papilloma of choroid plexus Diseases 0.000 claims 1
- 206010061332 Paraganglion neoplasm Diseases 0.000 claims 1
- 208000031839 Peripheral nerve sheath tumour malignant Diseases 0.000 claims 1
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 claims 1
- 206010034811 Pharyngeal cancer Diseases 0.000 claims 1
- 206010050487 Pinealoblastoma Diseases 0.000 claims 1
- 208000007641 Pinealoma Diseases 0.000 claims 1
- 208000021308 Pituicytoma Diseases 0.000 claims 1
- 201000005746 Pituitary adenoma Diseases 0.000 claims 1
- 206010061538 Pituitary tumour benign Diseases 0.000 claims 1
- 208000007452 Plasmacytoma Diseases 0.000 claims 1
- 208000035416 Prolymphocytic B-Cell Leukemia Diseases 0.000 claims 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 claims 1
- 208000034541 Rare lymphatic malformation Diseases 0.000 claims 1
- 208000015634 Rectal Neoplasms Diseases 0.000 claims 1
- 206010038389 Renal cancer Diseases 0.000 claims 1
- 208000006265 Renal cell carcinoma Diseases 0.000 claims 1
- 208000033889 Renal medullary carcinoma Diseases 0.000 claims 1
- 201000000582 Retinoblastoma Diseases 0.000 claims 1
- 208000005678 Rhabdomyoma Diseases 0.000 claims 1
- 208000025316 Richter syndrome Diseases 0.000 claims 1
- 208000006938 Schwannomatosis Diseases 0.000 claims 1
- 201000010208 Seminoma Diseases 0.000 claims 1
- 208000003274 Sertoli cell tumor Diseases 0.000 claims 1
- 208000009359 Sezary Syndrome Diseases 0.000 claims 1
- 208000021388 Sezary disease Diseases 0.000 claims 1
- 208000003252 Signet Ring Cell Carcinoma Diseases 0.000 claims 1
- 208000000453 Skin Neoplasms Diseases 0.000 claims 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 claims 1
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 claims 1
- 206010042971 T-cell lymphoma Diseases 0.000 claims 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 claims 1
- 208000020982 T-lymphoblastic lymphoma Diseases 0.000 claims 1
- 208000024313 Testicular Neoplasms Diseases 0.000 claims 1
- 201000000331 Testicular germ cell cancer Diseases 0.000 claims 1
- 206010057644 Testis cancer Diseases 0.000 claims 1
- 206010043515 Throat cancer Diseases 0.000 claims 1
- 208000024770 Thyroid neoplasm Diseases 0.000 claims 1
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 claims 1
- 208000008385 Urogenital Neoplasms Diseases 0.000 claims 1
- 201000005969 Uveal melanoma Diseases 0.000 claims 1
- 208000014070 Vestibular schwannoma Diseases 0.000 claims 1
- 206010047741 Vulval cancer Diseases 0.000 claims 1
- 208000004354 Vulvar Neoplasms Diseases 0.000 claims 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 claims 1
- 208000021146 Warthin tumor Diseases 0.000 claims 1
- 208000000260 Warts Diseases 0.000 claims 1
- 208000008383 Wilms tumor Diseases 0.000 claims 1
- 208000012018 Yolk sac tumor Diseases 0.000 claims 1
- 208000006336 acinar cell carcinoma Diseases 0.000 claims 1
- 208000004064 acoustic neuroma Diseases 0.000 claims 1
- 230000001154 acute effect Effects 0.000 claims 1
- 208000021841 acute erythroid leukemia Diseases 0.000 claims 1
- 208000013593 acute megakaryoblastic leukemia Diseases 0.000 claims 1
- 208000020700 acute megakaryocytic leukemia Diseases 0.000 claims 1
- 208000002517 adenoid cystic carcinoma Diseases 0.000 claims 1
- 208000026562 adenomatoid odontogenic tumor Diseases 0.000 claims 1
- 201000008395 adenosquamous carcinoma Diseases 0.000 claims 1
- 208000020990 adrenal cortex carcinoma Diseases 0.000 claims 1
- 201000005188 adrenal gland cancer Diseases 0.000 claims 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 claims 1
- 208000007128 adrenocortical carcinoma Diseases 0.000 claims 1
- 201000006966 adult T-cell leukemia Diseases 0.000 claims 1
- 208000015230 aggressive NK-cell leukemia Diseases 0.000 claims 1
- 206010065867 alveolar rhabdomyosarcoma Diseases 0.000 claims 1
- 208000008524 alveolar soft part sarcoma Diseases 0.000 claims 1
- 230000002707 ameloblastic effect Effects 0.000 claims 1
- 206010002449 angioimmunoblastic T-cell lymphoma Diseases 0.000 claims 1
- 201000009036 biliary tract cancer Diseases 0.000 claims 1
- 208000020790 biliary tract neoplasm Diseases 0.000 claims 1
- 201000009076 bladder urachal carcinoma Diseases 0.000 claims 1
- 201000000053 blastoma Diseases 0.000 claims 1
- 201000011143 bone giant cell tumor Diseases 0.000 claims 1
- 210000000845 cartilage Anatomy 0.000 claims 1
- 208000030748 clear cell sarcoma of kidney Diseases 0.000 claims 1
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 claims 1
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 0.000 claims 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims 1
- 201000004428 dysembryoplastic neuroepithelial tumor Diseases 0.000 claims 1
- 201000008184 embryoma Diseases 0.000 claims 1
- 208000001991 endodermal sinus tumor Diseases 0.000 claims 1
- 210000003754 fetus Anatomy 0.000 claims 1
- 201000003444 follicular lymphoma Diseases 0.000 claims 1
- 201000010175 gallbladder cancer Diseases 0.000 claims 1
- 201000008361 ganglioneuroma Diseases 0.000 claims 1
- 201000008822 gestational choriocarcinoma Diseases 0.000 claims 1
- 208000005017 glioblastoma Diseases 0.000 claims 1
- 208000003064 gonadoblastoma Diseases 0.000 claims 1
- 201000002222 hemangioblastoma Diseases 0.000 claims 1
- 208000006359 hepatoblastoma Diseases 0.000 claims 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims 1
- 206010066957 hepatosplenic T-cell lymphoma Diseases 0.000 claims 1
- 201000004933 in situ carcinoma Diseases 0.000 claims 1
- 201000002313 intestinal cancer Diseases 0.000 claims 1
- 206010073096 invasive lobular breast carcinoma Diseases 0.000 claims 1
- 201000010982 kidney cancer Diseases 0.000 claims 1
- 208000020319 kidney medullary carcinoma Diseases 0.000 claims 1
- 206010023841 laryngeal neoplasm Diseases 0.000 claims 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 claims 1
- 206010024627 liposarcoma Diseases 0.000 claims 1
- 201000007270 liver cancer Diseases 0.000 claims 1
- 208000014018 liver neoplasm Diseases 0.000 claims 1
- 208000012804 lymphangiosarcoma Diseases 0.000 claims 1
- 201000009020 malignant peripheral nerve sheath tumor Diseases 0.000 claims 1
- 208000015179 malignant superior sulcus neoplasm Diseases 0.000 claims 1
- 201000001117 malignant triton tumor Diseases 0.000 claims 1
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 claims 1
- 208000021937 marginal zone lymphoma Diseases 0.000 claims 1
- 208000000516 mast-cell leukemia Diseases 0.000 claims 1
- 208000029586 mediastinal germ cell tumor Diseases 0.000 claims 1
- 208000030163 medullary breast carcinoma Diseases 0.000 claims 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 claims 1
- 206010027191 meningioma Diseases 0.000 claims 1
- 230000001394 metastastic effect Effects 0.000 claims 1
- 206010061289 metastatic neoplasm Diseases 0.000 claims 1
- 208000022669 mucinous neoplasm Diseases 0.000 claims 1
- 201000009368 muscle benign neoplasm Diseases 0.000 claims 1
- 201000005987 myeloid sarcoma Diseases 0.000 claims 1
- 208000009091 myxoma Diseases 0.000 claims 1
- 208000001611 myxosarcoma Diseases 0.000 claims 1
- 208000014761 nasopharyngeal type undifferentiated carcinoma Diseases 0.000 claims 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 claims 1
- 208000007538 neurilemmoma Diseases 0.000 claims 1
- 201000009494 neurilemmomatosis Diseases 0.000 claims 1
- 208000027831 neuroepithelial neoplasm Diseases 0.000 claims 1
- 208000029974 neurofibrosarcoma Diseases 0.000 claims 1
- 201000000032 nodular malignant melanoma Diseases 0.000 claims 1
- 201000008106 ocular cancer Diseases 0.000 claims 1
- 206010073131 oligoastrocytoma Diseases 0.000 claims 1
- 208000027500 optic nerve neoplasm Diseases 0.000 claims 1
- 201000011130 optic nerve sheath meningioma Diseases 0.000 claims 1
- 208000022982 optic pathway glioma Diseases 0.000 claims 1
- 201000008968 osteosarcoma Diseases 0.000 claims 1
- 208000007312 paraganglioma Diseases 0.000 claims 1
- 201000002628 peritoneum cancer Diseases 0.000 claims 1
- 206010035059 pineocytoma Diseases 0.000 claims 1
- 208000021310 pituitary gland adenoma Diseases 0.000 claims 1
- 208000010916 pituitary tumor Diseases 0.000 claims 1
- 208000024246 polyembryoma Diseases 0.000 claims 1
- 208000016800 primary central nervous system lymphoma Diseases 0.000 claims 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 claims 1
- 206010038038 rectal cancer Diseases 0.000 claims 1
- 201000001275 rectum cancer Diseases 0.000 claims 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims 1
- 201000007416 salivary gland adenoid cystic carcinoma Diseases 0.000 claims 1
- 206010039667 schwannoma Diseases 0.000 claims 1
- 208000028467 sex cord-stromal tumor Diseases 0.000 claims 1
- 201000008123 signet ring cell adenocarcinoma Diseases 0.000 claims 1
- 201000000849 skin cancer Diseases 0.000 claims 1
- 201000010153 skin papilloma Diseases 0.000 claims 1
- 208000000649 small cell carcinoma Diseases 0.000 claims 1
- 201000002314 small intestine cancer Diseases 0.000 claims 1
- 239000004071 soot Substances 0.000 claims 1
- 208000037959 spinal tumor Diseases 0.000 claims 1
- 206010062113 splenic marginal zone lymphoma Diseases 0.000 claims 1
- 206010042863 synovial sarcoma Diseases 0.000 claims 1
- 201000003120 testicular cancer Diseases 0.000 claims 1
- 208000001644 thecoma Diseases 0.000 claims 1
- 201000002510 thyroid cancer Diseases 0.000 claims 1
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 claims 1
- 208000019179 thyroid gland undifferentiated (anaplastic) carcinoma Diseases 0.000 claims 1
- 201000007363 trachea carcinoma Diseases 0.000 claims 1
- 208000025443 tumor of adipose tissue Diseases 0.000 claims 1
- 208000037964 urogenital cancer Diseases 0.000 claims 1
- 206010046766 uterine cancer Diseases 0.000 claims 1
- 206010046885 vaginal cancer Diseases 0.000 claims 1
- 208000013139 vaginal neoplasm Diseases 0.000 claims 1
- 208000008662 verrucous carcinoma Diseases 0.000 claims 1
- 201000005102 vulva cancer Diseases 0.000 claims 1
- 230000008439 repair process Effects 0.000 abstract description 6
- 230000006378 damage Effects 0.000 abstract description 2
- 102000011724 DNA Repair Enzymes Human genes 0.000 abstract 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 124
- 239000000090 biomarker Substances 0.000 description 73
- 230000000694 effects Effects 0.000 description 46
- 230000014509 gene expression Effects 0.000 description 38
- 230000002401 inhibitory effect Effects 0.000 description 25
- 239000000523 sample Substances 0.000 description 23
- 230000003247 decreasing effect Effects 0.000 description 22
- 239000000203 mixture Substances 0.000 description 21
- 102000004169 proteins and genes Human genes 0.000 description 21
- 230000008685 targeting Effects 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 18
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 18
- 229960004748 abacavir Drugs 0.000 description 17
- 229960002555 zidovudine Drugs 0.000 description 17
- 230000035772 mutation Effects 0.000 description 16
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 16
- 229960000980 entecavir Drugs 0.000 description 15
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 15
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 13
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 13
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 13
- XNRVGTHNYCNCFF-UHFFFAOYSA-N Lapatinib ditosylate monohydrate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1.O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 XNRVGTHNYCNCFF-UHFFFAOYSA-N 0.000 description 13
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 11
- 102100029766 DNA polymerase theta Human genes 0.000 description 11
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 11
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 11
- IKKXOSBHLYMWAE-QRPMWFLTSA-N islatravir Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@H]1C[C@H](O)[C@](CO)(C#C)O1 IKKXOSBHLYMWAE-QRPMWFLTSA-N 0.000 description 11
- 229940121573 islatravir Drugs 0.000 description 11
- 210000001519 tissue Anatomy 0.000 description 11
- 101000865085 Homo sapiens DNA polymerase theta Proteins 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 229960002656 didanosine Drugs 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- 108020004414 DNA Proteins 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 101001094659 Homo sapiens DNA polymerase kappa Proteins 0.000 description 9
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 9
- 229940042992 afinitor Drugs 0.000 description 9
- 229960000366 emtricitabine Drugs 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 229960001627 lamivudine Drugs 0.000 description 9
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 9
- 230000006780 non-homologous end joining Effects 0.000 description 9
- 239000008194 pharmaceutical composition Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 238000003757 reverse transcription PCR Methods 0.000 description 9
- 229940045513 CTLA4 antagonist Drugs 0.000 description 8
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 8
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 description 8
- 101001068133 Homo sapiens Hepatitis A virus cellular receptor 2 Proteins 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 230000007423 decrease Effects 0.000 description 8
- 229960003804 efavirenz Drugs 0.000 description 8
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 229960000689 nevirapine Drugs 0.000 description 8
- 230000037361 pathway Effects 0.000 description 8
- 108090000765 processed proteins & peptides Proteins 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 229960001355 tenofovir disoproxil Drugs 0.000 description 8
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 description 8
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 description 7
- 210000001744 T-lymphocyte Anatomy 0.000 description 7
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 238000003782 apoptosis assay Methods 0.000 description 7
- 230000001419 dependent effect Effects 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- 238000003752 polymerase chain reaction Methods 0.000 description 7
- 230000005522 programmed cell death Effects 0.000 description 7
- LDEKQSIMHVQZJK-CAQYMETFSA-N tenofovir alafenamide Chemical compound O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-CAQYMETFSA-N 0.000 description 7
- 229960004946 tenofovir alafenamide Drugs 0.000 description 7
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 7
- 230000018412 transposition, RNA-mediated Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HSBKFSPNDWWPSL-VDTYLAMSSA-N 4-amino-5-fluoro-1-[(2s,5r)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@@H]1C=C[C@H](CO)O1 HSBKFSPNDWWPSL-VDTYLAMSSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 101000865099 Homo sapiens DNA-directed DNA/RNA polymerase mu Proteins 0.000 description 6
- 102000017578 LAG3 Human genes 0.000 description 6
- 229960003205 adefovir dipivoxil Drugs 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 229950006528 elvucitabine Drugs 0.000 description 6
- 150000002632 lipids Chemical class 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 102000004196 processed proteins & peptides Human genes 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical group C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 6
- 229960004556 tenofovir Drugs 0.000 description 6
- 101000981336 Homo sapiens Nibrin Proteins 0.000 description 5
- 108091034117 Oligonucleotide Proteins 0.000 description 5
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 5
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 230000001028 anti-proliverative effect Effects 0.000 description 5
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 239000012634 fragment Substances 0.000 description 5
- 238000009396 hybridization Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 230000010534 mechanism of action Effects 0.000 description 5
- 229920001184 polypeptide Polymers 0.000 description 5
- 108010014186 ras Proteins Proteins 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 229960005311 telbivudine Drugs 0.000 description 5
- IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- YJZSUCFGHXQWDM-UHFFFAOYSA-N 1-adamantyl 4-[(2,5-dihydroxyphenyl)methylamino]benzoate Chemical compound OC1=CC=C(O)C(CNC=2C=CC(=CC=2)C(=O)OC23CC4CC(CC(C4)C2)C3)=C1 YJZSUCFGHXQWDM-UHFFFAOYSA-N 0.000 description 4
- WVXRAFOPTSTNLL-NKWVEPMBSA-N 2',3'-dideoxyadenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1CC[C@@H](CO)O1 WVXRAFOPTSTNLL-NKWVEPMBSA-N 0.000 description 4
- OCLZPNCLRLDXJC-NTSWFWBYSA-N 2-amino-9-[(2r,5s)-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1CC[C@@H](CO)O1 OCLZPNCLRLDXJC-NTSWFWBYSA-N 0.000 description 4
- 108700040618 BRCA1 Genes Proteins 0.000 description 4
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 4
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 4
- 239000012275 CTLA-4 inhibitor Substances 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- 101710113864 Heat shock protein 90 Proteins 0.000 description 4
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 description 4
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 102000029749 Microtubule Human genes 0.000 description 4
- 108091022875 Microtubule Proteins 0.000 description 4
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 4
- 230000003321 amplification Effects 0.000 description 4
- 108091007433 antigens Proteins 0.000 description 4
- 102000036639 antigens Human genes 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 229910052681 coesite Inorganic materials 0.000 description 4
- 239000003246 corticosteroid Substances 0.000 description 4
- 229910052906 cristobalite Inorganic materials 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 230000001973 epigenetic effect Effects 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 229960002411 imatinib Drugs 0.000 description 4
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 4
- KBEMFSMODRNJHE-JFWOZONXSA-N lodenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)C[C@@H]1F KBEMFSMODRNJHE-JFWOZONXSA-N 0.000 description 4
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 210000004688 microtubule Anatomy 0.000 description 4
- 229950010895 midostaurin Drugs 0.000 description 4
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 description 4
- 201000006417 multiple sclerosis Diseases 0.000 description 4
- 238000003199 nucleic acid amplification method Methods 0.000 description 4
- 230000002611 ovarian Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 229910052682 stishovite Inorganic materials 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 229910052905 tridymite Inorganic materials 0.000 description 4
- 239000001226 triphosphate Substances 0.000 description 4
- 235000011178 triphosphate Nutrition 0.000 description 4
- 125000002264 triphosphate group Chemical class [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 description 4
- 230000035899 viability Effects 0.000 description 4
- ROIYOHMMVFSTAJ-SKWCMTHISA-N 4-amino-1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)-5-methyloxolan-2-yl]pyrimidin-2-one Chemical compound C1[C@H](O)[C@@](C)(CO)O[C@H]1N1C(=O)N=C(N)C=C1 ROIYOHMMVFSTAJ-SKWCMTHISA-N 0.000 description 3
- AKPDHAWHXJDZHO-JVUFJMBOSA-N 4-amino-1-[(2r,4s,5r)-5-ethyl-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound C1[C@H](O)[C@@](CC)(CO)O[C@H]1N1C(=O)N=C(N)C=C1 AKPDHAWHXJDZHO-JVUFJMBOSA-N 0.000 description 3
- 108091006112 ATPases Proteins 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 3
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 3
- 102100026376 Artemin Human genes 0.000 description 3
- 102000002804 Ataxia Telangiectasia Mutated Proteins Human genes 0.000 description 3
- 108010004586 Ataxia Telangiectasia Mutated Proteins Proteins 0.000 description 3
- 101700002522 BARD1 Proteins 0.000 description 3
- 102100028048 BRCA1-associated RING domain protein 1 Human genes 0.000 description 3
- 108091009167 Bloom syndrome protein Proteins 0.000 description 3
- 208000031404 Chromosome Aberrations Diseases 0.000 description 3
- 230000033616 DNA repair Effects 0.000 description 3
- 102100033996 Double-strand break repair protein MRE11 Human genes 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 102000018825 Fanconi Anemia Complementation Group C protein Human genes 0.000 description 3
- 102100027285 Fanconi anemia group B protein Human genes 0.000 description 3
- 102100034554 Fanconi anemia group I protein Human genes 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101000785776 Homo sapiens Artemin Proteins 0.000 description 3
- 101000591400 Homo sapiens Double-strand break repair protein MRE11 Proteins 0.000 description 3
- 101100119754 Homo sapiens FANCL gene Proteins 0.000 description 3
- 101000777293 Homo sapiens Serine/threonine-protein kinase Chk1 Proteins 0.000 description 3
- 101000777277 Homo sapiens Serine/threonine-protein kinase Chk2 Proteins 0.000 description 3
- 101000702545 Homo sapiens Transcription activator BRG1 Proteins 0.000 description 3
- 101000804798 Homo sapiens Werner syndrome ATP-dependent helicase Proteins 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 108060004795 Methyltransferase Proteins 0.000 description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 3
- 238000000636 Northern blotting Methods 0.000 description 3
- 239000012270 PD-1 inhibitor Substances 0.000 description 3
- 239000012668 PD-1-inhibitor Substances 0.000 description 3
- 108091008606 PDGF receptors Proteins 0.000 description 3
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 3
- 102100031081 Serine/threonine-protein kinase Chk1 Human genes 0.000 description 3
- 102100031075 Serine/threonine-protein kinase Chk2 Human genes 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 102100031027 Transcription activator BRG1 Human genes 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 102100035336 Werner syndrome ATP-dependent helicase Human genes 0.000 description 3
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 3
- CTDUJDNZPPZTAV-FSDSQADBSA-N [(2r,3r,5r)-5-(6-aminopurin-9-yl)-3-fluorooxolan-2-yl]methanol Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1C[C@@H](F)[C@@H](CO)O1 CTDUJDNZPPZTAV-FSDSQADBSA-N 0.000 description 3
- 238000009098 adjuvant therapy Methods 0.000 description 3
- 230000001772 anti-angiogenic effect Effects 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000000481 breast Anatomy 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 210000001072 colon Anatomy 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 230000005782 double-strand break Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 230000007614 genetic variation Effects 0.000 description 3
- 230000002489 hematologic effect Effects 0.000 description 3
- 230000002779 inactivation Effects 0.000 description 3
- 102000006639 indoleamine 2,3-dioxygenase Human genes 0.000 description 3
- 108020004201 indoleamine 2,3-dioxygenase Proteins 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 229960001428 mercaptopurine Drugs 0.000 description 3
- 229960001156 mitoxantrone Drugs 0.000 description 3
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 3
- 238000009099 neoadjuvant therapy Methods 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 230000002246 oncogenic effect Effects 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 229940121655 pd-1 inhibitor Drugs 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 210000002307 prostate Anatomy 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 210000003289 regulatory T cell Anatomy 0.000 description 3
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical class C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 102000003390 tumor necrosis factor Human genes 0.000 description 3
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- UMGQVUWXNOJOSJ-KMHUVPDISA-N (e)-2-cyano-3-(3,4-dihydroxyphenyl)-n-[(1r)-1-phenylethyl]prop-2-enamide Chemical compound N([C@H](C)C=1C=CC=CC=1)C(=O)C(\C#N)=C\C1=CC=C(O)C(O)=C1 UMGQVUWXNOJOSJ-KMHUVPDISA-N 0.000 description 2
- NSMOSDAEGJTOIQ-UHFFFAOYSA-N 2-(hydroxymethyl)oxolan-3-ol Chemical compound OCC1OCCC1O NSMOSDAEGJTOIQ-UHFFFAOYSA-N 0.000 description 2
- CYHSHMQZLJWIQQ-UHFFFAOYSA-N 2-(hydroxymethyl)oxolane-2-carbonitrile Chemical compound OCC1(CCCO1)C#N CYHSHMQZLJWIQQ-UHFFFAOYSA-N 0.000 description 2
- NHFDRBXTEDBWCZ-ZROIWOOFSA-N 3-[2,4-dimethyl-5-[(z)-(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrol-3-yl]propanoic acid Chemical compound OC(=O)CCC1=C(C)NC(\C=C/2C3=CC=CC=C3NC\2=O)=C1C NHFDRBXTEDBWCZ-ZROIWOOFSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- HSBKFSPNDWWPSL-CAHLUQPWSA-N 4-amino-5-fluoro-1-[(2r,5s)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1C=C[C@@H](CO)O1 HSBKFSPNDWWPSL-CAHLUQPWSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 229940122361 Bisphosphonate Drugs 0.000 description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 2
- 102100031065 Choline kinase alpha Human genes 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 2
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 2
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 102100031780 Endonuclease Human genes 0.000 description 2
- 108091008794 FGF receptors Proteins 0.000 description 2
- 229940124226 Farnesyltransferase inhibitor Drugs 0.000 description 2
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 2
- 208000031448 Genomic Instability Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 102400000932 Gonadoliberin-1 Human genes 0.000 description 2
- 101150106864 HR gene Proteins 0.000 description 2
- 101500026183 Homo sapiens Gonadoliberin-1 Proteins 0.000 description 2
- 101000619640 Homo sapiens Leucine-rich repeats and immunoglobulin-like domains protein 1 Proteins 0.000 description 2
- 101001128138 Homo sapiens NACHT, LRR and PYD domains-containing protein 2 Proteins 0.000 description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 2
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 2
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 2
- 108010005716 Interferon beta-1a Proteins 0.000 description 2
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 2
- 102000015335 Ku Autoantigen Human genes 0.000 description 2
- 108010025026 Ku Autoantigen Proteins 0.000 description 2
- 229940125563 LAG3 inhibitor Drugs 0.000 description 2
- 229940124761 MMP inhibitor Drugs 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 101710181812 Methionine aminopeptidase Proteins 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- 102100031897 NACHT, LRR and PYD domains-containing protein 2 Human genes 0.000 description 2
- 201000004253 NUT midline carcinoma Diseases 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- 101710163270 Nuclease Proteins 0.000 description 2
- 229940123527 Nucleotide reverse transcriptase inhibitor Drugs 0.000 description 2
- 238000012408 PCR amplification Methods 0.000 description 2
- 239000012271 PD-L1 inhibitor Substances 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 239000002033 PVDF binder Substances 0.000 description 2
- 229940079156 Proteasome inhibitor Drugs 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 108090000315 Protein Kinase C Proteins 0.000 description 2
- 102000003923 Protein Kinase C Human genes 0.000 description 2
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 2
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 239000013614 RNA sample Substances 0.000 description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000006044 T cell activation Effects 0.000 description 2
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 2
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 2
- 108010017842 Telomerase Proteins 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 2
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 2
- 102000016548 Vascular Endothelial Growth Factor Receptor-1 Human genes 0.000 description 2
- RLAHNGKRJJEIJL-RFZPGFLSSA-N [(2r,4r)-4-(2,6-diaminopurin-9-yl)-1,3-dioxolan-2-yl]methanol Chemical compound C12=NC(N)=NC(N)=C2N=CN1[C@H]1CO[C@@H](CO)O1 RLAHNGKRJJEIJL-RFZPGFLSSA-N 0.000 description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Chemical group C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 230000002280 anti-androgenic effect Effects 0.000 description 2
- 229940046836 anti-estrogen Drugs 0.000 description 2
- 230000001833 anti-estrogenic effect Effects 0.000 description 2
- 230000000340 anti-metabolite Effects 0.000 description 2
- 239000000051 antiandrogen Substances 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
- 239000002256 antimetabolite Substances 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 239000003886 aromatase inhibitor Substances 0.000 description 2
- 229950002916 avelumab Drugs 0.000 description 2
- 229960002170 azathioprine Drugs 0.000 description 2
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000008512 biological response Effects 0.000 description 2
- 150000004663 bisphosphonates Chemical class 0.000 description 2
- 229940127093 camptothecin Drugs 0.000 description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
- GYSSRZJIHXQEHQ-UHFFFAOYSA-N carboxin Chemical compound S1CCOC(C)=C1C(=O)NC1=CC=CC=C1 GYSSRZJIHXQEHQ-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 239000000328 estrogen antagonist Substances 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical class N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 2
- 102000054766 genetic haplotypes Human genes 0.000 description 2
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 2
- 229960001442 gonadorelin Drugs 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- 239000003481 heat shock protein 90 inhibitor Substances 0.000 description 2
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 229960000908 idarubicin Drugs 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 238000003018 immunoassay Methods 0.000 description 2
- 238000010166 immunofluorescence Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229960005386 ipilimumab Drugs 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 231100000225 lethality Toxicity 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 210000002751 lymph Anatomy 0.000 description 2
- 229940124302 mTOR inhibitor Drugs 0.000 description 2
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 239000003607 modifier Substances 0.000 description 2
- 231100000219 mutagenic Toxicity 0.000 description 2
- 230000003505 mutagenic effect Effects 0.000 description 2
- XGXNTJHZPBRBHJ-UHFFFAOYSA-N n-phenylpyrimidin-2-amine Chemical class N=1C=CC=NC=1NC1=CC=CC=C1 XGXNTJHZPBRBHJ-UHFFFAOYSA-N 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 231100000590 oncogenic Toxicity 0.000 description 2
- 229940121656 pd-l1 inhibitor Drugs 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 2
- 102000054765 polymorphisms of proteins Human genes 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 2
- 239000003207 proteasome inhibitor Substances 0.000 description 2
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 2
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 2
- 238000003127 radioimmunoassay Methods 0.000 description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 2
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 2
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 229960001940 sulfasalazine Drugs 0.000 description 2
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 2
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 2
- 239000003277 telomerase inhibitor Substances 0.000 description 2
- 229960001278 teniposide Drugs 0.000 description 2
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 229950007217 tremelimumab Drugs 0.000 description 2
- 229960000523 zalcitabine Drugs 0.000 description 2
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 1
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- JHXLLEDIXXOJQD-WELGVCPWSA-N (2-decoxy-3-dodecylsulfanylpropyl) [(2r,3s,5r)-3-fluoro-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl hydrogen phosphate Chemical compound C1[C@H](F)[C@@H](COP(O)(=O)OCC(CSCCCCCCCCCCCC)OCCCCCCCCCC)O[C@H]1N1C(=O)NC(=O)C(C)=C1 JHXLLEDIXXOJQD-WELGVCPWSA-N 0.000 description 1
- UZGFETRYZHMOTM-QRPMWFLTSA-N (2R,3S,5R)-5-(2,6-diaminopurin-9-yl)-2-ethenyl-2-(hydroxymethyl)oxolan-3-ol Chemical compound NC=1N=C(C=2N=CN([C@H]3C[C@H](O)[C@@](CO)(O3)C=C)C=2N=1)N UZGFETRYZHMOTM-QRPMWFLTSA-N 0.000 description 1
- PISJLYJYHHTLQQ-QRPMWFLTSA-N (2R,3S,5R)-5-(2,6-diaminopurin-9-yl)-2-ethyl-2-(hydroxymethyl)oxolan-3-ol Chemical compound CC[C@]1(CO)O[C@H](C[C@@H]1O)n1cnc2c(N)nc(N)nc12 PISJLYJYHHTLQQ-QRPMWFLTSA-N 0.000 description 1
- WOFZQOCKSAPKFH-SKWCMTHISA-N (2r,3s,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxy-2-(hydroxymethyl)oxolane-2-carbonitrile Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@@](CO)(C#N)[C@@H](O)C1 WOFZQOCKSAPKFH-SKWCMTHISA-N 0.000 description 1
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 1
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- GSQOBTOAOGXIFL-LFIBNONCSA-N (e)-2-cyano-3-(3,4-dihydroxyphenyl)-n-(3-phenylpropyl)prop-2-enamide Chemical compound C1=C(O)C(O)=CC=C1\C=C(/C#N)C(=O)NCCCC1=CC=CC=C1 GSQOBTOAOGXIFL-LFIBNONCSA-N 0.000 description 1
- GWCNJMUSWLTSCW-SFQUDFHCSA-N (e)-2-cyano-3-(3,4-dihydroxyphenyl)-n-(4-phenylbutyl)prop-2-enamide Chemical compound C1=C(O)C(O)=CC=C1\C=C(/C#N)C(=O)NCCCCC1=CC=CC=C1 GWCNJMUSWLTSCW-SFQUDFHCSA-N 0.000 description 1
- BQCIDUSAKPWEOX-UHFFFAOYSA-N 1,1-Difluoroethene Chemical compound FC(F)=C BQCIDUSAKPWEOX-UHFFFAOYSA-N 0.000 description 1
- MHWLGEGZFMYHPW-VAOFZXAKSA-N 1-[(2r,4s,5r)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-fluoropyrimidine-2,4-dione Chemical compound C1[C@H](O)[C@](CO)(C#C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 MHWLGEGZFMYHPW-VAOFZXAKSA-N 0.000 description 1
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 1
- ZADWXFSZEAPBJS-JTQLQIEISA-N 1-methyl-L-tryptophan Chemical compound C1=CC=C2N(C)C=C(C[C@H](N)C(O)=O)C2=C1 ZADWXFSZEAPBJS-JTQLQIEISA-N 0.000 description 1
- ZESRJSPZRDMNHY-YFWFAHHUSA-N 11-deoxycorticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 ZESRJSPZRDMNHY-YFWFAHHUSA-N 0.000 description 1
- DBPWSSGDRRHUNT-CEGNMAFCSA-N 17α-hydroxyprogesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DBPWSSGDRRHUNT-CEGNMAFCSA-N 0.000 description 1
- LXFQSRIDYRFTJW-UHFFFAOYSA-M 2,4,6-trimethylbenzenesulfonate Chemical compound CC1=CC(C)=C(S([O-])(=O)=O)C(C)=C1 LXFQSRIDYRFTJW-UHFFFAOYSA-M 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical class NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 1
- VTJXFTPMFYAJJU-UHFFFAOYSA-N 2-[(3,4-dihydroxyphenyl)methylidene]propanedinitrile Chemical compound OC1=CC=C(C=C(C#N)C#N)C=C1O VTJXFTPMFYAJJU-UHFFFAOYSA-N 0.000 description 1
- LKBXWNYXDMSFQU-ONNFQVAWSA-N 2-[2-[4-[[(e)-3-(4-bromophenyl)prop-2-enoyl]amino]-3-fluorophenyl]-1,3-benzoxazol-5-yl]acetic acid Chemical compound N=1C2=CC(CC(=O)O)=CC=C2OC=1C(C=C1F)=CC=C1NC(=O)\C=C\C1=CC=C(Br)C=C1 LKBXWNYXDMSFQU-ONNFQVAWSA-N 0.000 description 1
- FSPQCTGGIANIJZ-UHFFFAOYSA-N 2-[[(3,4-dimethoxyphenyl)-oxomethyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)NC1=C(C(N)=O)C(CCCC2)=C2S1 FSPQCTGGIANIJZ-UHFFFAOYSA-N 0.000 description 1
- MPCMLKLBMSFTTJ-QRPMWFLTSA-N 2-amino-9-[(2r,4s,5r)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1C[C@H](O)[C@](CO)(C#C)O1 MPCMLKLBMSFTTJ-QRPMWFLTSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- UZFPOOOQHWICKY-UHFFFAOYSA-N 3-[13-[1-[1-[8,12-bis(2-carboxyethyl)-17-(1-hydroxyethyl)-3,7,13,18-tetramethyl-21,24-dihydroporphyrin-2-yl]ethoxy]ethyl]-18-(2-carboxyethyl)-8-(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(=C(C)C(C=C4N5)=N3)CCC(O)=O)=N2)C)=C(C)C(C(C)O)=C1C=C5C(C)=C4C(C)OC(C)C1=C(N2)C=C(N3)C(C)=C(C(O)C)C3=CC(C(C)=C3CCC(O)=O)=NC3=CC(C(CCC(O)=O)=C3C)=NC3=CC2=C1C UZFPOOOQHWICKY-UHFFFAOYSA-N 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 1
- QSFREBZMBNRGOK-UHFFFAOYSA-N 4-[(2,5-dihydroxyphenyl)methylamino]benzoic acid methyl ester Chemical compound C1=CC(C(=O)OC)=CC=C1NCC1=CC(O)=CC=C1O QSFREBZMBNRGOK-UHFFFAOYSA-N 0.000 description 1
- LTZZZXXIKHHTMO-UHFFFAOYSA-N 4-[[4-fluoro-3-[4-(4-fluorobenzoyl)piperazine-1-carbonyl]phenyl]methyl]-2H-phthalazin-1-one Chemical compound FC1=C(C=C(CC2=NNC(C3=CC=CC=C23)=O)C=C1)C(=O)N1CCN(CC1)C(C1=CC=C(C=C1)F)=O LTZZZXXIKHHTMO-UHFFFAOYSA-N 0.000 description 1
- VERWQPYQDXWOGT-LVJNJWHOSA-N 4-amino-5-fluoro-1-[(2r,5s)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one;[[(2r)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate;(e)-but-2-enedioic acid Chemical compound OC(=O)\C=C\C(O)=O.C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VERWQPYQDXWOGT-LVJNJWHOSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 description 1
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- PBCZSGKMGDDXIJ-HQCWYSJUSA-N 7-hydroxystaurosporine Chemical compound N([C@H](O)C1=C2C3=CC=CC=C3N3C2=C24)C(=O)C1=C2C1=CC=CC=C1N4[C@H]1C[C@@H](NC)[C@@H](OC)[C@]3(C)O1 PBCZSGKMGDDXIJ-HQCWYSJUSA-N 0.000 description 1
- PBCZSGKMGDDXIJ-UHFFFAOYSA-N 7beta-hydroxystaurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3C(O)NC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 PBCZSGKMGDDXIJ-UHFFFAOYSA-N 0.000 description 1
- JJTNLWSCFYERCK-UHFFFAOYSA-N 7h-pyrrolo[2,3-d]pyrimidine Chemical class N1=CN=C2NC=CC2=C1 JJTNLWSCFYERCK-UHFFFAOYSA-N 0.000 description 1
- AOTRIQLYUAFVSC-UHFFFAOYSA-N 8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[4,5-c]quinolin-2-one Chemical group CN(CCCOC1=CC=C(C=N1)C1=CC=2C3=C(C=NC2C=C1)N(C(N3C3CCOCC3)=O)C)C AOTRIQLYUAFVSC-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 229940126253 ADU-S100 Drugs 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 1
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- UXCAQJAQSWSNPQ-XLPZGREQSA-N Alovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](F)C1 UXCAQJAQSWSNPQ-XLPZGREQSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 229940097396 Aminopeptidase inhibitor Drugs 0.000 description 1
- 108091093088 Amplicon Proteins 0.000 description 1
- YUWPMEXLKGOSBF-GACAOOTBSA-N Anecortave acetate Chemical compound O=C1CC[C@]2(C)C3=CC[C@]4(C)[C@](C(=O)COC(=O)C)(O)CC[C@H]4[C@@H]3CCC2=C1 YUWPMEXLKGOSBF-GACAOOTBSA-N 0.000 description 1
- 102400000068 Angiostatin Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- 229940122815 Aromatase inhibitor Drugs 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- CLGJCTXUWJLYHO-UHFFFAOYSA-N CSC1=C(Cl)C=CC2=C1N(CC(O)=O)C1=C(C=CC(=C1)C(C)(C)C)C2=O Chemical compound CSC1=C(Cl)C=CC2=C1N(CC(O)=O)C1=C(C=CC(=C1)C(C)(C)C)C2=O CLGJCTXUWJLYHO-UHFFFAOYSA-N 0.000 description 1
- 101100360207 Caenorhabditis elegans rla-1 gene Proteins 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 229920001268 Cholestyramine Polymers 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 102100031162 Collagen alpha-1(XVIII) chain Human genes 0.000 description 1
- OMFXVFTZEKFJBZ-UHFFFAOYSA-N Corticosterone Natural products O=C1CCC2(C)C3C(O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 OMFXVFTZEKFJBZ-UHFFFAOYSA-N 0.000 description 1
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 1
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 1
- 229940122204 Cyclooxygenase inhibitor Drugs 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 206010067477 Cytogenetic abnormality Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 108010032250 DNA polymerase beta2 Proteins 0.000 description 1
- 102100029765 DNA polymerase lambda Human genes 0.000 description 1
- 108010093204 DNA polymerase theta Proteins 0.000 description 1
- 229940123323 DNA repair enzyme inhibitor Drugs 0.000 description 1
- 102100027828 DNA repair protein XRCC4 Human genes 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- 102100022204 DNA-dependent protein kinase catalytic subunit Human genes 0.000 description 1
- 102100027700 DNA-directed RNA polymerase I subunit RPA2 Human genes 0.000 description 1
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 101100010303 Drosophila melanogaster PolG1 gene Proteins 0.000 description 1
- 108010079505 Endostatins Proteins 0.000 description 1
- 102400001368 Epidermal growth factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 1
- 229940124602 FDA-approved drug Drugs 0.000 description 1
- 102100034553 Fanconi anemia group J protein Human genes 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010082772 GFB 111 Proteins 0.000 description 1
- 101710113436 GTPase KRas Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 1
- 108010072051 Glatiramer Acetate Proteins 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 229920002971 Heparan sulfate Polymers 0.000 description 1
- 102100024025 Heparanase Human genes 0.000 description 1
- 229940122588 Heparanase inhibitor Drugs 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 102000008157 Histone Demethylases Human genes 0.000 description 1
- 108010074870 Histone Demethylases Proteins 0.000 description 1
- 102000003893 Histone acetyltransferases Human genes 0.000 description 1
- 108090000246 Histone acetyltransferases Proteins 0.000 description 1
- 108090000353 Histone deacetylase Proteins 0.000 description 1
- 102000003964 Histone deacetylase Human genes 0.000 description 1
- 108010016918 Histone-Lysine N-Methyltransferase Proteins 0.000 description 1
- 102000000581 Histone-lysine N-methyltransferase Human genes 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000600756 Homo sapiens 3-phosphoinositide-dependent protein kinase 1 Proteins 0.000 description 1
- 101000927810 Homo sapiens DNA ligase 4 Proteins 0.000 description 1
- 101001094607 Homo sapiens DNA polymerase eta Proteins 0.000 description 1
- 101000649315 Homo sapiens DNA repair protein XRCC4 Proteins 0.000 description 1
- 101000619536 Homo sapiens DNA-dependent protein kinase catalytic subunit Proteins 0.000 description 1
- 101000650600 Homo sapiens DNA-directed RNA polymerase I subunit RPA2 Proteins 0.000 description 1
- 101000940871 Homo sapiens Endonuclease Proteins 0.000 description 1
- 101000848171 Homo sapiens Fanconi anemia group J protein Proteins 0.000 description 1
- 101001066676 Homo sapiens Integrase Proteins 0.000 description 1
- 101001066681 Homo sapiens Integrase Proteins 0.000 description 1
- 101001066682 Homo sapiens Integrase Proteins 0.000 description 1
- 101001066686 Homo sapiens Integrase Proteins 0.000 description 1
- 101001066687 Homo sapiens Integrase Proteins 0.000 description 1
- 101001066688 Homo sapiens Integrase Proteins 0.000 description 1
- 101001066689 Homo sapiens Integrase Proteins 0.000 description 1
- 101001067009 Homo sapiens Integrase Proteins 0.000 description 1
- 101000624643 Homo sapiens M-phase inducer phosphatase 3 Proteins 0.000 description 1
- 101000578059 Homo sapiens Non-homologous end-joining factor 1 Proteins 0.000 description 1
- 101000757232 Homo sapiens Protein arginine N-methyltransferase 2 Proteins 0.000 description 1
- 101000720958 Homo sapiens Protein artemis Proteins 0.000 description 1
- 101000579425 Homo sapiens Proto-oncogene tyrosine-protein kinase receptor Ret Proteins 0.000 description 1
- 101000580039 Homo sapiens Ras-specific guanine nucleotide-releasing factor 1 Proteins 0.000 description 1
- 101001092206 Homo sapiens Replication protein A 32 kDa subunit Proteins 0.000 description 1
- 101001066690 Homo sapiens Ribonuclease H Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 101001117146 Homo sapiens [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010020843 Hyperthermia Diseases 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 101150091030 ITM2B gene Proteins 0.000 description 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 1
- 102000037978 Immune checkpoint receptors Human genes 0.000 description 1
- 108091008028 Immune checkpoint receptors Proteins 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 102100023350 Integral membrane protein 2B Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 241000764238 Isis Species 0.000 description 1
- 102000010638 Kinesin Human genes 0.000 description 1
- 108010063296 Kinesin Proteins 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 1
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229940123917 Lipid kinase inhibitor Drugs 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 102100020862 Lymphocyte activation gene 3 protein Human genes 0.000 description 1
- 102100023330 M-phase inducer phosphatase 3 Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 229940124647 MEK inhibitor Drugs 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102100027754 Mast/stem cell growth factor receptor Kit Human genes 0.000 description 1
- 101710087603 Mast/stem cell growth factor receptor Kit Proteins 0.000 description 1
- 102000016397 Methyltransferase Human genes 0.000 description 1
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 1
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 1
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 description 1
- 108010047290 Multifunctional Enzymes Proteins 0.000 description 1
- 102000006833 Multifunctional Enzymes Human genes 0.000 description 1
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- GPVKLYONJSSZFL-UHFFFAOYSA-N NSC 750259 Natural products CCC(C)C=CC(O)C(O)C(O)C(OC)C(=O)NC1CCCCNC1=O GPVKLYONJSSZFL-UHFFFAOYSA-N 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 102100028156 Non-homologous end-joining factor 1 Human genes 0.000 description 1
- MBJMCOJMDMARNB-UHFFFAOYSA-N O.O.O.O.[Na].[Na].OP(O)(=O)C(Cl)(Cl)P(O)(O)=O Chemical compound O.O.O.O.[Na].[Na].OP(O)(=O)C(Cl)(Cl)P(O)(O)=O MBJMCOJMDMARNB-UHFFFAOYSA-N 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 206010061534 Oesophageal squamous cell carcinoma Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 101150078890 POLG gene Proteins 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 1
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 1
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 102100025918 Protein artemis Human genes 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- 102100028286 Proto-oncogene tyrosine-protein kinase receptor Ret Human genes 0.000 description 1
- 101150025379 RPA1 gene Proteins 0.000 description 1
- 238000010240 RT-PCR analysis Methods 0.000 description 1
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 1
- 101710151245 Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 1
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 description 1
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 1
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 108091027967 Small hairpin RNA Proteins 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 102000004584 Somatomedin Receptors Human genes 0.000 description 1
- 108010017622 Somatomedin Receptors Proteins 0.000 description 1
- 208000036765 Squamous cell carcinoma of the esophagus Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- JXAGDPXECXQWBC-LJQANCHMSA-N Tanomastat Chemical compound C([C@H](C(=O)O)CC(=O)C=1C=CC(=CC=1)C=1C=CC(Cl)=CC=1)SC1=CC=CC=C1 JXAGDPXECXQWBC-LJQANCHMSA-N 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 229940123582 Telomerase inhibitor Drugs 0.000 description 1
- 108091033399 Telomestatin Proteins 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- DKJJVAGXPKPDRL-UHFFFAOYSA-N Tiludronic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)SC1=CC=C(Cl)C=C1 DKJJVAGXPKPDRL-UHFFFAOYSA-N 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 102100037236 Tyrosine-protein kinase receptor UFO Human genes 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 241000382509 Vania Species 0.000 description 1
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 1
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- UGWQMIXVUBLMAH-IVVFTGHFSA-N [(1s,4r)-4-[2-amino-6-(cyclopropylamino)purin-9-yl]cyclopent-2-en-1-yl]methanol;4-amino-1-[(2r,5s)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 UGWQMIXVUBLMAH-IVVFTGHFSA-N 0.000 description 1
- QBDVVYNLLXGUGN-XGTBZJOHSA-N [(3r,4s,5s,6r)-5-methoxy-4-[(2r,3r)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl] n-[(2r)-1-amino-3-methyl-1-oxobutan-2-yl]carbamate Chemical compound C([C@H]([C@H]([C@@H]1[C@]2(C)[C@H](O2)CC=C(C)C)OC)OC(=O)N[C@H](C(C)C)C(N)=O)C[C@@]21CO2 QBDVVYNLLXGUGN-XGTBZJOHSA-N 0.000 description 1
- ODEDPKNSRBCSDO-UHFFFAOYSA-N [2-(hexadecylsulfanylmethyl)-3-methoxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCCSCC(COC)COP([O-])(=O)OCC[N+](C)(C)C ODEDPKNSRBCSDO-UHFFFAOYSA-N 0.000 description 1
- 102100024148 [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial Human genes 0.000 description 1
- 229940030360 abacavir / lamivudine Drugs 0.000 description 1
- 229940114030 abacavir / lamivudine / zidovudine Drugs 0.000 description 1
- 229960002184 abarelix Drugs 0.000 description 1
- 108010023617 abarelix Proteins 0.000 description 1
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical compound C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- FHEAIOHRHQGZPC-KIWGSFCNSA-N acetic acid;(2s)-2-amino-3-(4-hydroxyphenyl)propanoic acid;(2s)-2-aminopentanedioic acid;(2s)-2-aminopropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound CC(O)=O.C[C@H](N)C(O)=O.NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CCC(O)=O.OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 FHEAIOHRHQGZPC-KIWGSFCNSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229960001997 adefovir Drugs 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- 229960004343 alendronic acid Drugs 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 229950004424 alovudine Drugs 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- 229950005846 amdoxovir Drugs 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000001195 anabolic effect Effects 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 229960001232 anecortave Drugs 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 238000000137 annealing Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 150000004056 anthraquinones Chemical class 0.000 description 1
- 238000011224 anti-cancer immunotherapy Methods 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 239000000063 antileukemic agent Substances 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 229940125688 antiparkinson agent Drugs 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- RYMCFYKJDVMSIR-RNFRBKRXSA-N apricitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1S[C@H](CO)OC1 RYMCFYKJDVMSIR-RNFRBKRXSA-N 0.000 description 1
- 229950007936 apricitabine Drugs 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 238000003491 array Methods 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 229950004810 atamestane Drugs 0.000 description 1
- PEPMWUSGRKINHX-TXTPUJOMSA-N atamestane Chemical compound C1C[C@@H]2[C@@]3(C)C(C)=CC(=O)C=C3CC[C@H]2[C@@H]2CCC(=O)[C@]21C PEPMWUSGRKINHX-TXTPUJOMSA-N 0.000 description 1
- 229940068561 atripla Drugs 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 229940003504 avonex Drugs 0.000 description 1
- 108010023337 axl receptor tyrosine kinase Proteins 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- 229940002637 baraclude Drugs 0.000 description 1
- 229950001858 batimastat Drugs 0.000 description 1
- XFILPEOLDIKJHX-QYZOEREBSA-N batimastat Chemical compound C([C@@H](C(=O)NC)NC(=O)[C@H](CC(C)C)[C@H](CSC=1SC=CC=1)C(=O)NO)C1=CC=CC=C1 XFILPEOLDIKJHX-QYZOEREBSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229930195545 bengamide Natural products 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 238000002725 brachytherapy Methods 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 description 1
- 229960005539 bryostatin 1 Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 229950002826 canertinib Drugs 0.000 description 1
- OMZCMEYTWSXEPZ-UHFFFAOYSA-N canertinib Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 description 1
- QTAOMKOIBXZKND-PPHPATTJSA-N carbidopa Chemical compound O.NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 QTAOMKOIBXZKND-PPHPATTJSA-N 0.000 description 1
- 229960004205 carbidopa Drugs 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- OHUHVTCQTUDPIJ-JYCIKRDWSA-N ceralasertib Chemical group C[C@@H]1COCCN1C1=CC(C2(CC2)[S@](C)(=N)=O)=NC(C=2C=3C=CNC=3N=CC=2)=N1 OHUHVTCQTUDPIJ-JYCIKRDWSA-N 0.000 description 1
- ZXFCRFYULUUSDW-OWXODZSWSA-N chembl2104970 Chemical compound C([C@H]1C2)C3=CC=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2CC(O)=C(C(=O)N)C1=O ZXFCRFYULUUSDW-OWXODZSWSA-N 0.000 description 1
- ZGHQGWOETPXKLY-XVNBXDOJSA-N chembl77030 Chemical compound NC(=S)C(\C#N)=C\C1=CC=C(O)C(O)=C1 ZGHQGWOETPXKLY-XVNBXDOJSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 229960002286 clodronic acid Drugs 0.000 description 1
- 108091008033 coinhibitory receptors Proteins 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000002153 concerted effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 1
- 230000000139 costimulatory effect Effects 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000000315 cryotherapy Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 108091007930 cytoplasmic receptors Proteins 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- ZESRJSPZRDMNHY-UHFFFAOYSA-N de-oxy corticosterone Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 ZESRJSPZRDMNHY-UHFFFAOYSA-N 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000001335 demethylating effect Effects 0.000 description 1
- 238000000326 densiometry Methods 0.000 description 1
- 230000000779 depleting effect Effects 0.000 description 1
- 229940090272 descovy Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229960003654 desoxycortone Drugs 0.000 description 1
- 230000000368 destabilizing effect Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229950009751 dexelvucitabine Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 229950006700 edatrexate Drugs 0.000 description 1
- FSIRXIHZBIXHKT-MHTVFEQDSA-N edatrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CC(CC)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FSIRXIHZBIXHKT-MHTVFEQDSA-N 0.000 description 1
- 238000010894 electron beam technology Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 229940083713 emtricitabine / tenofovir alafenamide Drugs 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000009261 endocrine therapy Methods 0.000 description 1
- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 description 1
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 1
- JRURYQJSLYLRLN-BJMVGYQFSA-N entacapone Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-BJMVGYQFSA-N 0.000 description 1
- 229960003337 entacapone Drugs 0.000 description 1
- QDGZDCVAUDNJFG-FXQIFTODSA-N entecavir (anhydrous) Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)C1=C QDGZDCVAUDNJFG-FXQIFTODSA-N 0.000 description 1
- 108060002566 ephrin Proteins 0.000 description 1
- 102000012803 ephrin Human genes 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 229930013356 epothilone Natural products 0.000 description 1
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 1
- 229940019131 epzicom Drugs 0.000 description 1
- GTTBEUCJPZQMDZ-UHFFFAOYSA-N erlotinib hydrochloride Chemical compound [H+].[Cl-].C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 GTTBEUCJPZQMDZ-UHFFFAOYSA-N 0.000 description 1
- 208000007276 esophageal squamous cell carcinoma Diseases 0.000 description 1
- 229960003399 estrone Drugs 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-L ethane-1,2-disulfonate Chemical compound [O-]S(=O)(=O)CCS([O-])(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-L 0.000 description 1
- 229960004945 etoricoxib Drugs 0.000 description 1
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 229950011548 fadrozole Drugs 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960000556 fingolimod Drugs 0.000 description 1
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229960005304 fludarabine phosphate Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229940043075 fluocinolone Drugs 0.000 description 1
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 description 1
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 229960004421 formestane Drugs 0.000 description 1
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 108010074605 gamma-Globulins Proteins 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 229940093097 genvoya Drugs 0.000 description 1
- 229950009073 gimatecan Drugs 0.000 description 1
- UIVFUQKYVFCEKJ-OPTOVBNMSA-N gimatecan Chemical compound C1=CC=C2C(\C=N\OC(C)(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UIVFUQKYVFCEKJ-OPTOVBNMSA-N 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 229960003776 glatiramer acetate Drugs 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229960003690 goserelin acetate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 108010037536 heparanase Proteins 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 102000046485 human PRMT2 Human genes 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000036031 hyperthermia Effects 0.000 description 1
- 238000009217 hyperthermia therapy Methods 0.000 description 1
- 229960005236 ibandronic acid Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229950006905 ilmofosine Drugs 0.000 description 1
- 229960003685 imatinib mesylate Drugs 0.000 description 1
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 238000007901 in situ hybridization Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 229950001750 lonafarnib Drugs 0.000 description 1
- DHMTURDWPRKSOA-RUZDIDTESA-N lonafarnib Chemical compound C1CN(C(=O)N)CCC1CC(=O)N1CCC([C@@H]2C3=C(Br)C=C(Cl)C=C3CCC3=CC(Br)=CN=C32)CC1 DHMTURDWPRKSOA-RUZDIDTESA-N 0.000 description 1
- 229950008745 losoxantrone Drugs 0.000 description 1
- YROQEQPFUCPDCP-UHFFFAOYSA-N losoxantrone Chemical compound OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO YROQEQPFUCPDCP-UHFFFAOYSA-N 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 229960000994 lumiracoxib Drugs 0.000 description 1
- KHPKQFYUPIUARC-UHFFFAOYSA-N lumiracoxib Chemical compound OC(=O)CC1=CC(C)=CC=C1NC1=C(F)C=CC=C1Cl KHPKQFYUPIUARC-UHFFFAOYSA-N 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229950008959 marimastat Drugs 0.000 description 1
- OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 description 1
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- VPABMVYNSQRPBD-AOJMVMDXSA-N methyl (2r)-2-[[(4-bromophenoxy)-[[(2s,5r)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methoxy]phosphoryl]amino]propanoate Chemical compound N1([C@@H]2O[C@@H](C=C2)COP(=O)(N[C@H](C)C(=O)OC)OC=2C=CC(Br)=CC=2)C=C(C)C(=O)NC1=O VPABMVYNSQRPBD-AOJMVMDXSA-N 0.000 description 1
- 238000002493 microarray Methods 0.000 description 1
- 210000003879 microtubule-organizing center Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- VYGYNVZNSSTDLJ-HKCOAVLJSA-N monorden Natural products CC1CC2OC2C=C/C=C/C(=O)CC3C(C(=CC(=C3Cl)O)O)C(=O)O1 VYGYNVZNSSTDLJ-HKCOAVLJSA-N 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229960005127 montelukast Drugs 0.000 description 1
- 230000000869 mutational effect Effects 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- 210000000066 myeloid cell Anatomy 0.000 description 1
- YBTGTVGEKMZEQX-UHFFFAOYSA-N n-(4-bromo-2-fluorophenyl)-6-methoxy-7-[2-(triazol-1-yl)ethoxy]quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCN3N=NC=C3)C(OC)=CC2=C1NC1=CC=C(Br)C=C1F YBTGTVGEKMZEQX-UHFFFAOYSA-N 0.000 description 1
- BLCLNMBMMGCOAS-UHFFFAOYSA-N n-[1-[[1-[[1-[[1-[[1-[[1-[[1-[2-[(carbamoylamino)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amin Chemical compound C1CCC(C(=O)NNC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)C(COC(C)(C)C)NC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 BLCLNMBMMGCOAS-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 229950010159 nemorubicin Drugs 0.000 description 1
- CTMCWCONSULRHO-UHQPFXKFSA-N nemorubicin Chemical compound C1CO[C@H](OC)CN1[C@@H]1[C@H](O)[C@H](C)O[C@@H](O[C@@H]2C3=C(O)C=4C(=O)C5=C(OC)C=CC=C5C(=O)C=4C(O)=C3C[C@](O)(C2)C(=O)CO)C1 CTMCWCONSULRHO-UHQPFXKFSA-N 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960001346 nilotinib Drugs 0.000 description 1
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- KOSYAAIZOGNATQ-UHFFFAOYSA-N o-phenyl chloromethanethioate Chemical compound ClC(=S)OC1=CC=CC=C1 KOSYAAIZOGNATQ-UHFFFAOYSA-N 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 229940099809 odefsey Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- QNDVLZJODHBUFM-WFXQOWMNSA-N okadaic acid Chemical compound C([C@H](O1)[C@H](C)/C=C/[C@H]2CC[C@@]3(CC[C@H]4O[C@@H](C([C@@H](O)[C@@H]4O3)=C)[C@@H](O)C[C@H](C)[C@@H]3[C@@H](CC[C@@]4(OCCCC4)O3)C)O2)C(C)=C[C@]21O[C@H](C[C@@](C)(O)C(O)=O)CC[C@H]2O QNDVLZJODHBUFM-WFXQOWMNSA-N 0.000 description 1
- VEFJHAYOIAAXEU-UHFFFAOYSA-N okadaic acid Natural products CC(CC(O)C1OC2CCC3(CCC(O3)C=CC(C)C4CC(=CC5(OC(CC(C)(O)C(=O)O)CCC5O)O4)C)OC2C(O)C1C)C6OC7(CCCCO7)CCC6C VEFJHAYOIAAXEU-UHFFFAOYSA-N 0.000 description 1
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 1
- 229960003978 pamidronic acid Drugs 0.000 description 1
- 229960005415 pasireotide Drugs 0.000 description 1
- 108700017947 pasireotide Proteins 0.000 description 1
- NEEFMPSSNFRRNC-HQUONIRXSA-N pasireotide aspartate Chemical compound OC(=O)[C@@H](N)CC(O)=O.OC(=O)[C@@H](N)CC(O)=O.C([C@H]1C(=O)N2C[C@@H](C[C@H]2C(=O)N[C@H](C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@H](C(N[C@@H](CC=2C=CC(OCC=3C=CC=CC=3)=CC=2)C(=O)N1)=O)CCCCN)C=1C=CC=CC=1)OC(=O)NCCN)C1=CC=CC=C1 NEEFMPSSNFRRNC-HQUONIRXSA-N 0.000 description 1
- WVUNYSQLFKLYNI-AATRIKPKSA-N pelitinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC1=CC=C(F)C(Cl)=C1 WVUNYSQLFKLYNI-AATRIKPKSA-N 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 229960004851 pergolide Drugs 0.000 description 1
- YEHCICAEULNIGD-MZMPZRCHSA-N pergolide Chemical compound C1=CC([C@H]2C[C@@H](CSC)CN([C@@H]2C2)CCC)=C3C2=CNC3=C1 YEHCICAEULNIGD-MZMPZRCHSA-N 0.000 description 1
- SZFPYBIJACMNJV-UHFFFAOYSA-N perifosine Chemical compound CCCCCCCCCCCCCCCCCCOP([O-])(=O)OC1CC[N+](C)(C)CC1 SZFPYBIJACMNJV-UHFFFAOYSA-N 0.000 description 1
- 229950010632 perifosine Drugs 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- YYPUSXWRDIQUQE-UHFFFAOYSA-N phenoxymethanethioic s-acid Chemical compound OC(=S)OC1=CC=CC=C1 YYPUSXWRDIQUQE-UHFFFAOYSA-N 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 229950010773 pidilizumab Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical class [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 229960004293 porfimer sodium Drugs 0.000 description 1
- 229960003089 pramipexole Drugs 0.000 description 1
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 229950003608 prinomastat Drugs 0.000 description 1
- YKPYIPVDTNNYCN-INIZCTEOSA-N prinomastat Chemical compound ONC(=O)[C@H]1C(C)(C)SCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=NC=C1 YKPYIPVDTNNYCN-INIZCTEOSA-N 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 238000002331 protein detection Methods 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 238000002661 proton therapy Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- ZTHJULTYCAQOIJ-WXXKFALUSA-N quetiapine fumarate Chemical compound [H+].[H+].[O-]C(=O)\C=C\C([O-])=O.C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12.C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 ZTHJULTYCAQOIJ-WXXKFALUSA-N 0.000 description 1
- ZADWXFSZEAPBJS-UHFFFAOYSA-N racemic N-methyl tryptophan Natural products C1=CC=C2N(C)C=C(CC(N)C(O)=O)C2=C1 ZADWXFSZEAPBJS-UHFFFAOYSA-N 0.000 description 1
- AECPBJMOGBFQDN-YMYQVXQQSA-N radicicol Chemical compound C1CCCC(=O)C[C@H]2[C@H](Cl)C(=O)CC(=O)[C@H]2C(=O)O[C@H](C)C[C@H]2O[C@@H]21 AECPBJMOGBFQDN-YMYQVXQQSA-N 0.000 description 1
- 229930192524 radicicol Natural products 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960002119 raloxifene hydrochloride Drugs 0.000 description 1
- BKXVVCILCIUCLG-UHFFFAOYSA-N raloxifene hydrochloride Chemical compound [H+].[Cl-].C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 BKXVVCILCIUCLG-UHFFFAOYSA-N 0.000 description 1
- 229940038850 rebif Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000028617 response to DNA damage stimulus Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229960004181 riluzole Drugs 0.000 description 1
- 229960000759 risedronic acid Drugs 0.000 description 1
- 229940106887 risperdal Drugs 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- QXKJWHWUDVQATH-UHFFFAOYSA-N rogletimide Chemical compound C=1C=NC=CC=1C1(CC)CCC(=O)NC1=O QXKJWHWUDVQATH-UHFFFAOYSA-N 0.000 description 1
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 1
- 229950009213 rubitecan Drugs 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229950003647 semaxanib Drugs 0.000 description 1
- WUWDLXZGHZSWQZ-WQLSENKSSA-N semaxanib Chemical compound N1C(C)=CC(C)=C1\C=C/1C2=CC=CC=C2NC\1=O WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 description 1
- 229940035004 seroquel Drugs 0.000 description 1
- 210000004911 serous fluid Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 229960001203 stavudine Drugs 0.000 description 1
- 229940070590 stribild Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- UXXQOJXBIDBUAC-UHFFFAOYSA-N tandutinib Chemical compound COC1=CC2=C(N3CCN(CC3)C(=O)NC=3C=CC(OC(C)C)=CC=3)N=CN=C2C=C1OCCCN1CCCCC1 UXXQOJXBIDBUAC-UHFFFAOYSA-N 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- YVSQVYZBDXIXCC-INIZCTEOSA-N telomestatin Chemical compound N=1C2=COC=1C(N=1)=COC=1C(N=1)=COC=1C(N=1)=COC=1C(N=1)=COC=1C(=C(O1)C)N=C1C(=C(O1)C)N=C1[C@@]1([H])N=C2SC1 YVSQVYZBDXIXCC-INIZCTEOSA-N 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 description 1
- SVUJNSGGPUCLQZ-FQQAACOVSA-N tenofovir alafenamide fumarate Chemical compound OC(=O)\C=C\C(O)=O.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 SVUJNSGGPUCLQZ-FQQAACOVSA-N 0.000 description 1
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960005324 tiludronic acid Drugs 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 229950009158 tipifarnib Drugs 0.000 description 1
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 229960001670 trilostane Drugs 0.000 description 1
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 1
- SCHZCUMIENIQMY-UHFFFAOYSA-N tris(trimethylsilyl)silicon Chemical compound C[Si](C)(C)[Si]([Si](C)(C)C)[Si](C)(C)C SCHZCUMIENIQMY-UHFFFAOYSA-N 0.000 description 1
- 229940004491 triumeq Drugs 0.000 description 1
- 229940111527 trizivir Drugs 0.000 description 1
- 229940008349 truvada Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- TUCIOBMMDDOEMM-RIYZIHGNSA-N tyrphostin B42 Chemical compound C1=C(O)C(O)=CC=C1\C=C(/C#N)C(=O)NCC1=CC=CC=C1 TUCIOBMMDDOEMM-RIYZIHGNSA-N 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 229940111505 videx ec Drugs 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
- 229960002110 vincristine sulfate Drugs 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 1
- 229950009819 zotarolimus Drugs 0.000 description 1
- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 description 1
- 229940039925 zyprexa Drugs 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
- A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
Definitions
- the present disclosure is in the field of medicinal chemistry.
- the disclosure provides a method for treating cancer by administering a reverse transcriptase inhibitor (RTI), that is also a DNA polymerase theta (PolQ) inhibitor to a patient in need thereof whose cancer cells have a deficiency or is suspected of having a deficiency of a DNA repair enzyme.
- RTI reverse transcriptase inhibitor
- PolQ DNA polymerase theta
- RTIs include lamivudine (3TC), stavudine (d4T), emtricitabine (FTC), abacavir (ABC), tenofovir alafenamide, zidovudine (AZT), didanosine (ddl), tenofovir disoproxil, adefovir dipivoxil, entecavir (ETV), and telbivudine.
- the RTI is a nucleoside reverse transciptase inhibitor (NRTI).
- NRTI nucleoside reverse transciptase inhibitor
- the disclosure also provides a method for treating cancer by administering a damage repair (DDR) enzyme inhibitor, e.g. a Pol ⁇ , Pol ⁇ , and/or Pol ⁇ inhibitor.
- the cancer is breast, colon, lung, pancreatic ductal, prostate, ovarian, or head and neck cancer.
- DSBs DNA double-strand breaks
- HR homologous recombination
- NHEJ non-homologous end-joining
- alt-NHEJ alternative NHEJ
- MMEJ Microhomology-mediated end-joining
- HR-mediated repair is a high-fidelity mechanism essential for accurate error-free repair, preventing cancer-predisposing genomic stability.
- NHEJ and MMEJ are error-prone pathways that can leave mutational scars at the site of repair.
- MMEJ can function parallel to both HR and NHEJ pathways (Truong et al. PNAS 2013, 110 (19), 7720-7725). See also WO2021/123785.
- PolQ UniProtKB - 075417 (DPOLQ HUMAN) as the key protein in MMEJ (Kent et al., Nature Structural & Molecular Biology’ (2015), 22(3), 230-237, Mateos-Gomez et al., Nature (2015), 518(7538), 254-257).
- PolQ is multifunctional enzyme, which comprises an N-terminal helicase domain (SF2 HEL308-type) and a C-terminal low-fidelity DNA polymerase domain (A-type) (Wood & D bountye, DNA Repair (2016), 44, 22-32). Both domains have been shown to have concerted mechanistic functions in MMEJ.
- the helicase domain mediates the removal of RPA protein from ssDNA ends and stimulates annealing.
- the polymerase domain extends the ssDNA ends and fills the remaining gaps.
- PolQ has been shown to be essential for the survival of HR-defective (HRD) cells (e.g. synthetic lethal with FA/BRCA-deficiency) and is up-regulated in HRD tumor cell lines (Ceccaldi et al.. Nature (2015), 518(7538), 258-262).
- HRD HR-defective
- PolQ inhibition prevents the MMEJ -dependent functional reversion of BRCA2 mutations that underlies the emergence of cisplatin and PARPi resistance in tumors.
- DDR inhibitors e.g., a Pol ⁇ , Pol ⁇ , and/or Pol ⁇ inhibitor, for the treatment of cancer.
- a method of treating cancer in a patient comprising administering to the patient an effective amount of a reverse transcriptase inhibitor (RTI) that is also a Pol ⁇ inhibitor, with the proviso that the RTI is not ddC (also known as zalcitabine or 2'-3 '-dideoxy cytidine).
- RTI reverse transcriptase inhibitor
- a method of treating cancer in a patient comprising administering to the patient an effective amount of DDR enzyme, e.g., Pol0, inhibitor.
- DDR enzyme e.g., Pol0, inhibitor.
- a method of treating cancer in a patient wherein the cells of the cancer are suspected of or exhibit defi ciency of a DDR enzyme, comprising administering to the patient an effective amount of DDR enzyme, e.g., Pol0, inhibitor.
- DDR enzyme e.g., Pol0, inhibitor.
- a method of treating cancer in a patient comprising administering to the patient an effective amount of DDR enzyme, e.g., Pol0, inhibitor.
- DDR enzyme e.g., Pol0, inhibitor.
- a method of treating cancer in a patient wherein the cells of the cancer are suspected of or exhibit deficiency of a DNA repair enzyme, comprising administering to the patient an effective amount of DDR enzyme, e.g., PolG, inhibitor.
- DDR enzyme e.g., PolG
- the method further comprises administering a second agent that is a poly ADP ribose polymerase (PARI 5 ) inhibitor, an ATM inhibitor, a weel inhibitor, a CHK inhibitor, or an ATR inhibitor.
- a second agent that is a poly ADP ribose polymerase (PARI 5 ) inhibitor, an ATM inhibitor, a weel inhibitor, a CHK inhibitor, or an ATR inhibitor.
- the cells are resistant to PARP inhibition.
- the second agent is a PARP inhibitor.
- the PARP inhibitor is olaparib, rucaparib, niraparib or talazoparib.
- the DDR enzyme is encoded by at least one homologous recombination (HR) gene.
- the at least one HR gene is ATM, ,ATR, BRCA1, BRCA2, BARD1, RAD51C, RAD50, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 (FANCN), FANCP (BTBD12), ERCC4 (FANCQ), FPEN, CDK12, MRE11, NBS 1, NBN, CLASPIN, BLM, WRN, SMARCA2, SMARCA4 LIG1 , RPA1, BRIP1 or PTEN.
- HR homologous recombination
- the RTI is lamivudine (3TC), zidovudine (AZT), tenofovir, tenofovir disoproxil, tenofovir alafenamide, stavudine (d4T), didanosine (ddl), emtricitabine (FTC), entecavir (ETV), 2',3'-dideoxyguanosine (ddG), 2’,3’- dideoxyadenosine (ddA), 2'-fluoro-2',3'-dideoxyarabinosyladenine (F-ddA), efavirenz (EFV), nevirapine (NVP), abacavir (ABC), adefovir dipivoxil, or telbivudine.
- the RTI and/or DNA damage repair enzyme inhibitor is a compound of Formula I: or a pharmaceutically acceptable salt or solvate thereof, or
- [0015] B is selected from the group consisting of
- R 1 is selected from the group consisting of hydrogen and -OH;
- R 2 is selected from the group consisting of methyl, ethynyl, and -CN;
- R 3 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo and methyl;
- R 4 is selected from the group consisting of -NH 2 and -OH;
- R 3 is selected from the group consisting of -NH 2 and -OH;
- R 6 is selected from the group consisting of hydrogen, fluoro, chloro, and -NH 2
- the RTI and/or DNA damage repair enzyme inhibitor is a compound of Formula II: or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof, wherein R 1 , R”, R 3 , and R 4 are as defined in connection with Formula I.
- the RTI and/or DDR enzyme inhibitor is a compound of Formula II, wherein R 3 is hydrogen.
- the RTI and/or DDR enzyme inhibitor is a compound of Formula II, wherein R 3 is selected from the group consisting of fluoro and chloro. [0025] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound of Formula II, wherein R 3 is methyl.
- the RTI and/or DDR enzyme inhibitor is a compound of Formula II, wherein R 4 is -NH 2 .
- the RTI and/or DDR enzyme inhibitor is a compound of Formula II, wherein R 4 is -OH.
- the RTI and/or DDR enzyme inhibitor is a compound of Formula III: or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof, wherein R 1 , R 2 , R 5 , and R° are as defined in connection with Formula I.
- the RTI and/or DDR enzyme inhibitor is a compound of Formula III, wherein R 5 is -NH 2 .
- the RTI and/or DDR enzyme inhibitor is a compound of Formula III, wherein R 5 is -OH.
- the RTI and/or DDR enzyme inhibitor is a compound of Formula III, wherein R 6 is hydrogen.
- the RTI and/or DDR enzyme inhibitor is a compound of Formula III, wherein R 6 is chloro.
- the RTI and/or DDR enzyme inhibitor is a compound of Formula III, wherein R 6 is fluoro.
- the RTI and/or DDR enzyme inhibitor is a compound of Formula III, wherein R 6 is -NH 2 .
- the RTI and/or DDR enzyme inhibitor is a compound of any one of Formulae I-III, wherein R 1 is hydrogen.
- the RTI and/or DDR enzyme inhibitor is a compound of any one of Formulae I-III, wherein R 1 is -OH.
- the RTI and/or DDR enzyme inhibitor is a compound of any one of Formulae I-III, wherein R 2 is methyl.
- the RTI and/or DDR enzyme inhibitor is a compound of any one of Formulae I-III, wherein R 2 is ethynyl.
- the RTI and/or DDR enzyme inhibitor is a compound of any one of Formulae I-III, wherein R 2 is -CN.
- the RTI and/or DDR enzyme inhibitor is any one or more of the compounds of Table A, or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof
- the RTI and/or DDR enzyme inhibitor is any one or more of the compounds of Table B, or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof.
- the RTI and/or DDR enzyme inhibitor is a compound Table A, Table B, or Table 3. See below.
- the compound of Table A, Table B, or Table 3 is a RTI and a DDR enzyme inhibitor.
- the compound of Table A, Table B, or Table 3 is a RTI inhibitor.
- the compound of Table A, Table B, or Table 3 is a DDR enzyme inhibitor, e.g., one or more of the DDR enzymes of Table C.
- the compound of Table A, Table B, or Table 3 is a Pol ⁇ inhibitor.
- the compound of Table A, Table B, or Table 3 is a Pol ⁇ inhibitor.
- the compound of Table A, Table B, or Table 3 is a Pol ⁇ inhibitor.
- the compound of Table A, Table B, or Table 3 is a Pol ⁇ inhibitor.
- the DDR enzyme inhibitor is a compound of Table 3.
- the cancer i s breast cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCAI and/or BRCA2 genes.
- the cancer is prostate cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and or BRCA2 genes.
- the cancer is ovarian cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCAI and /or BRCA2 genes.
- the cancer is pancreatic cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCAI and/or BRCA2 genes.
- the cells of the cancer exhibit overexpression of PolQ compared to the corresponding cells that are not cancer cells.
- the RTI inhibits human LINE-1 retrotransposition with a half maximal inhibitor ⁇ ' concentration of less than 100 nM in a HeLa cell-based dualluciferase assay. In some embodiments, the RTI inhibits human LINE-1 retrotransposition with a half maximal inhibitory concentration of less than 50 nM in a HeLa cell-based dualluciferase assay. In some embodiments, the RTI inhibits human LINE-1 retrotransposition with a half maximal inhibitory concentration of less than 10 nM in a HeLa cell-based dualluciferase assay.
- the method further comprises administering a therapeutically effective amount of at least one second therapeutic agent useful for treating the cancer.
- the method is for the treatment of breast cancer, wherein the at least one second therapeutic agent is Soltamox® (tamoxifen), Arimidex® (anastrozole), Femara® (letrozole), Aromasin® (exemestane), Herceptin® (trastuzumab), Abraxane® (paclitaxel), Cytoxan® (cyclophosphamide), Taxol® (paclitaxel), Afinitor® (everolimus), Taxotere® (docetaxel), Xeloda® (capecitabine), Trexall® (methotrexate), Faslodex (fulvestrant), Adriamycin® (doxorubicin), Perjeta® (pertuzumab), Gemzar (gemcitabine), Tykerb® (lapatinib), Adrucil® (fluorouracil), Ibrance® (palbociclib), Verzenio® (abemaciclib), Fareston®
- Soltamox®
- the method is for the treatment of colon cancer, wherein the at least one second therapeutic agent is Xeloda® (capecitabine), Eloxatin® (oxaliplatin), fluorouracil, Avastin® (bevacizumab), leucovorin, Camptosar® (irinotecan), Stivarga® (regorafenib), Erbitux® (cetuximab), Vectibix® (panitumumab), Lonsurf® (tipiracil/trifluridine), Zaltrap® (ziv-aflibercept), Betaseron® (interferon beta-lb), Fusilev® (levoleucovorin), Wellcocorin® (methotrexate), Keytruda® (pembrolizumab), Mvasi® (bevacizumab-awwb), Cyramza® (ramucirumab), Yervoy® (ipilmumab
- the method is for the treatment of lung cancer, wherein the at least one second therapeutic agent is Etopophos® (etoposide), Hycamtin® (topotecan), VePesid® (etoposide), Toposar® (etoposide), Opdivo® (nivolumab), Keytruda® (pembrolizumab), Tecentriq® (atezolizumab), Imfinizi® (durvalumab), methotrexate, cyclophosphamide, Carboplatin, Cisplatin, docetaxel, Gemcitabine, Irinotecan, Paclitaxel, Pemetrexed, Vinblastine, or Vinorelbine.
- Etopophos® etoposide
- Hycamtin® topotecan
- VePesid® etoposide
- Toposar® etoposide
- Opdivo® nivolumab
- Keytruda® pembrolizumab
- the method is for the treatment of pancreatic ductal cancer, wherein the at least one second therapeutic agent is Gemzar® (Gemcitabine), fluorouracil, Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (irinotecan), bevacizumab, cetuximab, Infugem® (gemcitabine) or Lynparza® (olaparib).
- Gemzar® Gamcitabine
- fluorouracil Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin
- the method is for the treatment of head and neck cancer, wherein the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
- the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
- the method is for the treatment of prostate cancer, wherein the at least one second therapeutic agent is Suprefact® (buserelin), Firmagon® (degarelix), Zoladex® (goserelin), Vantas® (histrelin), Eligard® (leuprolide), Orgovyx® (relugolix), Trelstar® (triptorelin), Casodex® (bicalutamide), Eulexin® (flutamide), Nilandron® (nilutamide), Zytiga® (biraterone acetate), Erleada® (apalutamide), or Xtandi® (enzalutamide).
- Suprefact® buserelin
- Firmagon® degarelix
- Zoladex® goserelin
- Vantas® histrelin
- Eligard® leuprolide
- Orgovyx® relugolix
- Trelstar® triptorelin
- Casodex® (bicalutamide),
- the at least one second therapeutic agent is a STING agonist.
- the patient is (a) not infected with the HIV virus, (b) not suspected of being infected with the HIV virus, (c) not being treated for the HIV virus, and/or (d) not being treated to prevent the HIV virus.
- kits for carrying out the methods described herein comprising (i) a RTI and/or DDR enzyme inhibitor; and (ii) and instructions for administering the RTI and/or DDR enzyme inhibitor to a patient having cancer.
- the kit contains instructions for administering the RTI and/or DDR enzyme inhibitor according to an intermittent dosing schedule.
- the kit further comprises at least one second therapeutic agent for the treatment of cancer.
- the kit further comprises instructions for administering the RTI and/or DDR enzyme inhibitor together with at least one second therapeutic agent for the treatment of cancer.
- a method for treating cancer in patient in need thereof comprising administering a therapeutically effective amount of a reverse transcriptase inhibitor (RTI) that also inhibits PolQ, wherein the cells of the cancer are suspected of or exhibit deficiency of a DDR enzyme.
- RTI reverse transcriptase inhibitor
- the combination of, e.g., PolQ inhibition, and a deficiency of a DDR enzyme causes synthetic lethality to the cancer cells.
- the deficiency is a reduction in the activity of a DDR enzyme.
- the definiciency is an absence of activity of a DDR enzyme.
- the deficiency of the DDR enzyme may be caused any means that results in the deficiency of the DDR enzyme including, but not limited to, genetic variations of the gene encoding the DDR enzyme including mutations (e.g. point mutations), substitutions, deletions, single nucleotide polymorphisms (SNPs), haplotypes, chromosome abnormalities. Copy Number Variation (CNV), epigenetics, DNA inversions, reduction in expression and mis-localisation.
- a method of treating or preventing cancer in a patient in need thereof comprising administering a therapeutically effective amount of a DDR enzyme inhibitor to the patient.
- the DDR enzyme inhibitor is one or more of the DDR enzymes of Table C. In another embodiment, the DDR enzyme inhibitor is a Pol ⁇ , Pol ⁇ , or Pol ⁇ inhibitor. In one embodiment, the DDR enzyme inhibitor is a Pol ⁇ (PolQ) inhibitor. In some embodiments, the cancer is a homologous recombinant (HR) deficient cancer.
- said homologous recombination genes include any of: ATM, APR, BRCA1, BRCA2, BARD1, RAD51C, RAD50, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 (FANCN), FANCP (BTBDI2), ERCC4 (BANCO), PTEN, CDK12, MRE11, NBS1, NBN, CLASPIN, BLM, WRN SMARCA2, SMARCA4, LIGI , RPA 1, RPA2, BRI Pi and PTEN.
- the disclosure provides a method for treating cancer in subject in need thereof comprising administering a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Table A, Table B, or Table 3, e.g., a compound of Table 3, wherein the cells of the cancer are suspected of or exhibit amplification of a DDR enzyme or gene.
- a compound disclosed herein e.g., a compound of Table A, Table B, or Table 3, e.g., a compound of Table 3, wherein the cells of the cancer are suspected of or exhibit amplification of a DDR enzyme or gene.
- DDR gene amplification e.g., overexpression, can lead to chemotherapy resistance and poor overall survival by augmenting DDR. See, e.g., Wu et al., Theranostics 10:3939- 3951 (2020).
- Non-homologous end-joining deficiency refers to any genetic variation which results in a deficiency or loss of function of the resultant homologous recombination gene.
- examples of said genetic variation include mutations (e.g. point mutations), substitutions, deletions, single nucleotide polymorphisms (SNPs), haplotypes, chromosome abnormalities, Copy Number Variation (CNV), epigenetics, DNA inversions, reduction in expression and mis-localisation.
- said non-homologous end-joining genes are selected from any one or more of: LIG4, NHEJ1 , POLL, POLM, PRKDC, XRCC4, XRCC5, XRCC6, and DCLRE1C.
- the RTI is islatravir, elvucitabine, lamivudine (3TC), zidovudine (AZT), tenofovir, tenofovir disoproxil, tenofovir alafenamide, stavudine (d4T), didanosine (ddl), emtricitabine (FTC), entecavir (ETV) or abacavir (ABC), wherein the RTI is administered according to an intermittent dosing schedule.
- the RTI is abacavir (ZIAGENTM), abacavir/lamivudine (Epzicom), abacavir/lamivudine/zidovudine (TRIZIVIR TM ), adefovir, alovudine, amdoxovir, apricitabine, ATRIPLA®, BARACLUDE®, BIKT ARV Y®, COVIRACII.
- the RTI is a LINE-1 inhibitor.
- the RTI is islatravir, elvucitabine, lamivudine (3TC), zidovudine (AZT), tenofovir, tenofovir disoproxil, tenofovir alafenamide, stavudine (d4T), didanosine (ddl), emtricitabine (FTC), entecavir (ETV), 2',3’-dideoxyguanosine (ddG), 2', 3 '-dideoxyadenosine (ddA), 2'-fluoro-2',3 '-dideoxyarabinosyladenine (F-ddA), efavirenz (EFV), nevirapine (NVP), or abacavir (ABC).
- the RTI is lamivudine (3TC), stavudine (d4T), emtricitabine (FTC), abacavir (ABC), tenofovir alafenamide, zidovudine (AZT), didanosine (ddl), tenofovir disoproxil, adefovir dipivoxil, entecavir (ETV), or telbivudine.
- the RTI is islatravir.
- the RTI is lamivudine (3TC).
- the RTI is stavudine (d4T).
- the RTI is emtricitabine (FTC).
- the RTI is abacavir (ABC).
- the RTI is tenofovir alafenamide.
- the RTI is zidovudine (AZT).
- the RTI is didanosine (ddl).
- the RTI is tenofovir disoproxil.
- the RTI is adefovir dipivoxil. [0081] In another embodiment, the RTI is entecavir.
- the RTI is telbivudine.
- cancer e.g., breast, colon, king, pancreatic ductal, prostate, ovarian, or head and neck cancer
- Elvucitabine is a compound having the following chemical structure:
- RTI reverse transcriptase inhibitor
- IC 50 a nucleoside or nucleotide reverse transcriptase inhibitor.
- RTIs inhibit human reverse transcriptase activity, e.g., with an IC 50 of about 50 ⁇ M or less, a suitable assay, e.g., a colorimetric enzyme immunoassay.
- the IC 50 is 1 ⁇ M or less.
- the IC 50 is 0,5 ⁇ M or less.
- the IC 50 is 0.25 ⁇ M or less.
- the IC 50 is 0.15 ⁇ M or less.
- the IC 50 is 0.1 ⁇ M or less.
- the IC 50 is 0.05 ⁇ M or less. In another embodiment, the IC 50 is 0.01 ⁇ M or less. In another embodiment, the IC 50 is 0.005 ⁇ M or less.
- the RTI a nucleoside reverse transcriptase inhibitor (NRTI). In some embodiments, the RTI a nucleotide reverse transcriptase inhibitor. In some embodiments, the RTI is also a LINE-1 inhibitor.
- DNA repair enzyme inhibitor or "DDR enzyme inhibitor” and the like as used herein refers to a compound that inhibits the activity of one or more human DNA damage repair enzymes with a half-maximal inhibitory concentration (IC 50 ) of 100 ⁇ M or less.
- a DDR enzyme inhibitor inhibits human DDR enzyme activity an IC 50 of 10 ⁇ M or less.
- a DDR enzyme inhibitor inhibits human DDR enzyme activity with an IC 50 of 1 ⁇ M or less.
- a DDR enzyme inhibitor inhibits human DDR enzyme activity with an IC 50 of 500 nM or less.
- a DDR enzyme inhibitor inhibits human DDR enzyme activity with an IC 50 of 100 nM or less.
- a DDR enzyme inhibitor inhibits human DDR enzyme activity with an IC 50 of 50 nM or less. In another embodiment, a DDR enzyme inhibitor inhibits human DDR enzyme activity with an IC 50 of 10 nM or less.
- Representative DDR enzymes are encoded by genes provided in Table Al . Representative DDR inhibitors are provided, for example, in Table 3.
- the compounds disclosed herein may be phosphorylated in a cell by the addition of one, two, or three phosphate groups to form the corresponding mono, di-, or triphosphates as shown in Scheme 1 for Cpd. No. 2:
- these phosphorylated compounds inhibit DDR enzymes following admistration to a subject.
- these compounds can be used, for example, to treat or prevent cancers wherein DDR enzymes play a causative role.
- cancer cells often acquire mutations in DDR genes, making them dependent on remaining DNA repair pathways.
- Dependence on TMEJ for example, is characterized by an increased Pol ⁇ expression and is associated with poor patient prognosis.
- Inhibition of Pol ⁇ in Pol ⁇ -dependent cancers leads to synthetic lethality. This is well described for malignancies deficient in homologous recombination, e.g., due to mutations in BRCA1 or BRCA2. See, e.g., Schrempt et al., Trends in Cancer 7:98-111 (2021) https://d0i.0rg/l 0.1016/j .trecan.2020.09.007.
- a Compound of the Disclosure is synthetic lethal in cancers with HR or NHEJ deficiency
- PolQ inhibitor or " Pol ⁇ inhibitor” as used herein refers to a compound that inhibits human PolQ activity with a half-maximal inhibitory/ concentration (IC50) of 100 nM or less. In some embodiments, the PolQ inhibitor inhibits PolQ activity with an IC 50 of less than 50 nM. In other embodiments, the PolQ inhibitor inhibits PolQ activity with an IC 50 of less than 10 nM.
- a PolQ inhibitor assay is disclosed in WO2021/123785, the disclosure of which is fully incorporated by reference.
- the phosphorylated species of the compounds disclosed herein, see Scheme 1 are POLQ inhibitors.
- the triphosphates of the compounds disclosed herein are POLQ inhibitors. Representative triphosphates (TP) of the compounds disclosed herein are provided in Table 1 A.
- LINE-1 inhibitor refers to a compound that inhibits human LINE-1 retrotransposition, e.g., with an IC 50 of about 50 ⁇ M or less in a HeLa cellbased dual -luciferase assay. See also Jones et al., (2008) PLoS ONE 3(2): el 547. doi:10.1371/joumal. pone.0001547; Xie et al., (2011) Nucleic Acids Res. 39(3): e!6. doi: 10.1093/nar/gkql076.
- the IC 50 is 1 ⁇ M or less.
- the IC 50 is 0.5 ⁇ M or less.
- the IC 50 is 0.25 ⁇ M or less. In another embodiment, the IC 50 is 0.15 ⁇ M or less. In another embodiment, the IC50 is 0.1 ⁇ M or less. In another embodiment, the IC 50 is 0.05 ⁇ M or less. In another embodiment., the IC 50 is 0.01 ⁇ M or less. In another embodiment, the IC 50 is 0.005 ⁇ M or less.
- the LINE-1 inhibitor is also a nucleoside reverse transcriptase inhibitor (NRTI). In some embodiments, the LINE-1 inhibitor is also a PolQ inhibitor.
- Non-limiting exemplary LINE-1 inhibitors are described, for example, in WO 2020/154656 and Banuelos-Sanchez et al., Cell Chemical Biology 26:1095-1109 (2019).
- Non-limiting exemplary LINE-1 inhibitors include islatravir, elvucitabine, lamivudine (3TC), zidovudine (AZT), tenofovir, tenofovir disoproxil, tenofovir alaphenamide, stavudine (d4T), didanosine (ddl), emtricitabine (FTC), entecavir (ETV), 2',3'-dideoxyguanosine (ddG), 2', 3 '-dideoxyadenosine (ddA), 2'-fluoro-2',3 '-dideoxyarabinosy ladenine (F-ddA), efavirenz (EFV), nevirapine (NVP), and abacavir (AB
- biological sample refers any tissue or fluid from a subject that is suitable for detecting a biomarker.
- useful biological samples include, but are not limited to, biopsi ed tissues and/or cells, e.g., lymph gland, inflamed tissue, tissue and/or cells involved in a condition or disease, blood, plasma, serous fluid, cerebrospinal fluid, saliva, urine, lymph, cerebral spinal fluid, and the like.
- Other suitable biological samples will be familiar to those of ordinary skill in the relevant arts.
- a biological sample can be analyzed for the expression level of a biological compound, e.g., POLQ, using any technique known in the art.
- PCR polymerase chain reaction
- RT-PCR reverse transcription-polymerase chain reaction
- clg-FISH cytoplasmic light chain immunofluorescence combined with fluorescence in situ hybridization
- intermittent dose administration refers to non-continuous administration of a RTI and/or DDR enzyme inhibitor to a subject.
- Intermittent dose administration regimens useful in the present disclosure encompass any discontinuous administration regimen that provides a therapeutically effective amount of a RTI and/or DDR enzyme inhibitor to a subject in need thereof.
- Intermittent dosing regimens can use equivalent, lower, or higher doses of a RTI and/or DDR enzyme inhibitor than would be used in continuous dosing regimens.
- Advantages of intermittent dose administration include, but are not limited to, improved safety, decreased toxicity, e.g., decreased weight loss, increased exposure, increased efficacy, and/or increased subject compliance. These advantages may be realized when a RTI and/or DDR enzyme inhibitor is administered as a single agent or when administered in combination with one or more additional therapeutic agents, e.g., a STING agonist.
- Examples of treatable cancers include, but are not limited to, any one or more of the cancers of Table I .
- the cancer is a solid tumor.
- the cancer a hematological cancer.
- Exemplary hematological cancers include, but are not limited to, the cancers listed in Table 2.
- the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia.
- the cancer is a leukemia, for example a leukemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia and mixed lineage leukemia (MLL).
- the cancer is NUT-midline carcinoma.
- the cancer is multiple myeloma.
- the cancer is a lung cancer such as small cell lung cancer (SCLC).
- SCLC small cell lung cancer
- the cancer is a neuroblastoma.
- the cancer is Burkitt’s lymphoma.
- the cancer is cervical cancer.
- the cancer is esophageal cancer.
- the cancer is ovarian cancer.
- the cancer is colorectal cancer.
- the cancer is prostate cancer.
- the cancer is breast cancer.
- the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, breast cancer, bladder cancer, ovary' cancer, glioma, sarcoma, esophageal squamous cell carcinoma, and papillary thyroid carcinoma.
- islatravir is administered to a subj ect in need thereof to treat breast, colon, lung, pancreatic ductal, prostate, ovarian, or head and neck cancer.
- the cancer is breast cancer.
- the cancer is colon cancer.
- the cancer is lung cancer, e.g., small cell lung cancer or non-small cell lung cancer.
- the cancer is pancreatic ductal cancer.
- the cancer is prostate cancer.
- the cancer is ovarian cancer.
- the cancer is head and neck cancer.
- the cells of the cancer overexpress one or more DDR enzymes.
- the cells of the cancer overexpress one or more enzymes encoded by the genes of Table Bl.
- the cells of the cancer overexpress one or more DDR enzymes of Table C.
- the cancer overexpresses Pol ⁇ .
- the cancer overexpresses Pol ⁇ .
- the cancer overexpresses Pol g.
- the cancer overexpresses TdT.
- the cancer overexpresses POLQ.
- the cancer is breast cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and/or BRCA2 genes.
- the cancer is prostate cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and or BRCA2 genes.
- the cancer is ovarian cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and /or BRCA2 genes.
- the cancer is pancreatic cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and/or BRCA2 genes.
- the patient is also administered at least one second therapeutic agent useful for the treatment of cancer.
- the second therapeutic agent useful for the treatment of cancer is is a poly ADP ribose polymerase (PARP) inhibitor, an ATM inhibitor, a weel inhibitor, a CHK inhibitor, or an ATR inhibitor.
- PARP poly ADP ribose polymerase
- the PARP inhibitor is olaparib, rucaparib, niraparib or talazoparib.
- the ATM inhibitor is AZD0156 or M3541 .
- the ATR inhibitor is AZD6738, M4344, or M6620.
- the weel inhibitor is AZDI 775.
- the second therapeutic agent is an epigenetic drug.
- epigenetic drug refers to a therapeutic agent that targets an epigenetic regulator.
- epigenetic regulators include the histone lysine methyltransferases, histone arginine methyl transferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases.
- Histone deacetylase inhibitors include, but are not limited to, vorinostat.
- chemotherapeutic agents or other anti -proliferative agents can be combined with islatravir to treat proliferative diseases and cancer.
- therapies and anticancer agents that can be used in combination with islatravir include surgery, radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes), endocrine therapy, a biologic response modifier (e.g., an interferon, an interleukin, tumor necrosis factor (TNF), hyperthermia and cryotherapy, an agent to attenuate any adverse effect (e.g., an antiemetic), and any other approved chemotherapeutic drug.
- radiotherapy e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes
- endocrine therapy e.g., a biologic response modifier (e.g.,
- antiproliferative compounds include, but are not limited to, an aromatase inhibitor; an anti -estrogen, an anti -androgen; a gonadorelin agonist; a topoisomerase I inhibitor; a topoisomerase II inhibitor; a microtubule active agent; an alkylating agent; a retinoid, a carontenoid, or a tocopherol; a cyclooxygenase inhibitor; an MMP inhibitor; an mTOR inhibitor; an antimetabolite; a platin compound; a methionine aminopeptidase inhibitor; a bisphosphonate; an antiproliferative antibody; a heparanase inhibitor; an inhibitor of Ras oncogenic isoforms; a telomerase inhibitor; a proteasome inhibitor; a compound used in the treatment of hematologic malignancies; a Flt-3 inhibitor; an Hsp90 inhibitor; a kinesin spindle protein inhibitor
- Nonlimiting exemplary' aromatase inhibitors include, but are not limited to, steroids, such as atamestane, exemestane, and formestane, and non-steroids, such as aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole, and letrozole.
- steroids such as atamestane, exemestane, and formestane
- non-steroids such as aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole, and letrozole.
- Nonlimiting anti -estrogens include, but are not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride.
- Anti-androgens include, but are not limited to, bicalutamide.
- Gonadorelin agonists include, but are not limited to, abarelix, goserelin, and goserelin acetate.
- topoisomerase I inhibitors include, but are not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogues, 9-nitrocamptothecin, and the macromolecular camptothecin conjugate PNU-166148.
- Topoisomerase 11 inhibitors include, but are not limited to, anthracyclines, such as doxorubicin, daunorubicin, epirubicin, idarubicin, and nemorubicin; anthraquinones, such as mitoxantrone and losoxantrone; and podophillotoxines, such as etoposide and teniposide.
- Microtubule active agents include microtubule stabilizing, microtubule destabilizing compounds, and microtubulin polymerization inhibitors including, but not limited to, taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine, vinblastine sulfate, vincristine, and vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof.
- taxanes such as paclitaxel and docetaxel
- vinca alkaloids such as vinblastine, vinblastine sulfate, vincristine, and vincristine sulfate, and vinorelbine
- discodermolides such as cochicine and epothilones and derivatives thereof.
- Exemplary nonlimiting alkylating agents include cyclophosphamide, ifosfamide, melphalan, and nitrosoureas, such as carmustine and lomustine.
- Exemplary' nonlimiting cyclooxygenase inhibitors include Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib, rofecoxib, etoricoxib, valdecoxib, or a 5-alkyl-2-arylaminophenyl acetic acid, such as lumiracoxib.
- MMP inhibitors include collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, batimastat, marimastat, prinomastat, metastat, BMS-279251, BAY 12-9566, TAA211, MMI270B, and AAJ996.
- Exemplary nonlimiting mTOR inhibitors include compounds that inhibit the mammalian target of rapamycin (mTOR) and possess antiproliferative activity such as sirolimus, everolimus, CCI-779, and ABT578.
- mTOR mammalian target of rapamycin
- Exemplary' nonlimiting antimetabolites include 5-fluorouraci I (5-FU), capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists, such as pemetrexed.
- Exemplary' nonlimiting platin compounds include carboplatin, cis-platin, cisplatinum, and oxaliplatin.
- Exemplary nonlimiting methionine aminopeptidase inhibitors include bengamide or a derivative thereof and PPI-2458.
- Exemplary nonlimiting bisphosphonates include etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid.
- antiproliferative antibodies include trastuzumab, trastuzumab-DMl, cetuximab, bevacizumab, rituximab, PR064553, and 2C4.
- antibody is meant to include intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.
- Exemplary nonlimiting heparanase inhibitors include compounds that target, decrease, or inhibit heparin sulfate degradation, such as PI-88 and OGT2115.
- an inhibitor of Ras oncogenic isoforms such as H ⁇ Ras, K-Ras, or N- Ras, as used herein refers to a compound which targets, decreases, or inhibits the oncogenic activity of Ras, for example, a farnesyl transferase inhibitor, such as L-744832, DK8G557, tipifarnib, and lonafarnib.
- telomerase inhibitors include compounds that target, decrease, or inhibit the activity of telomerase, such as compounds that inhibit the telomerase receptor, such as telomestatin.
- telomestatin compounds that inhibit the telomerase receptor
- proteasome inhibitors include compounds that target, decrease, or inhibit the activity of the proteasome including, but not limited to, bortezomid.
- FMS-like tyrosine kinase inhibitors which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, I- ⁇ -D-arabinofuransylcytosine (ara-c), and bisulfan; and ALK inhibitors, which are compounds which target, decrease, or inhibit anaplastic lymphoma kinase.
- Exemplary nonlimiting Fit-3 inhibitors include PKC412, midostaurin, a staurosporine derivative, SU11248, and MLN518.
- Exemplary nonlimiting HSP90 inhibitors include compounds targeting, decreasing, or inhibiting the intrinsic ATPase activity of HSP90; or degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway.
- Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17- allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds, radicicol and HDAC inhibitors.
- a compound targeting/decreasing a protein or lipid kinase activity'; or a protein or lipid phosphatase activity; or any further anti -angiogenic compound includes a protein tyrosine kinase and/or serine and/or threonine kinase inhibitor or lipid kinase inhibitor, such as a) a compound targeting, decreasing, or inhibiting the activity of the platelet- deri ved growth factor-receptors (PDGFR), such as a compound that targets, decreases, or inhibits the activity of PDGFR, such as an N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SUIOI, SU6668, and GFB-111 , b) a compound targeting, decreasing, or inhibiting the activity of the fibroblast growth factor-receptors (FGFR); c) a compound targeting, decreasing, or inhibiting the activity of the insulin-
- PDGFR platelet- deri
- Bcr- Abl kinase and mutants, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib; PD180970; AG957; NSC 680410; PD173955; or dasatinib; j) a compound targeting, decreasing, or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and Ras/MAPK family members, and/or members of the cyclin-dependent kinase family (CDK), such as a staurosporine derivative disclosed in U.S.
- PKC protein kinase C
- Raf family of serine/threonine kinases members of the MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and Ras/MAPK family members,
- Patent No. 5,093,330 such as midostaurin
- examples of further compounds include UCN- 01, safingoi, BAY 43-9006, bryostatin 1, perifosine, ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; a isochinoline compound; a farnesyl transferase inhibitor; PD184352 or QAN697, or .AT7519; k) a compound targeting, decreasing or inhibiting the activity of a protein-tyrosine kinase, such as imatinib mesylate or a tyrphostin, such as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213, Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494
- Exemplary compounds that target, decrease, or inhibit the activity of a protein or lipid phosphatase include inhibitors of phosphatase 1, phosphatase 2 A, or CDC25, such as okadaic acid or a derivative thereof.
- Further anti-angiogenic compounds include compounds having another mechanism for their activity unrelated to protein or lipid kinase inhibition, e.g., thalidomide and TNP- 470.
- Additional, nonlimiting, exemplary chemotherapeutic compounds include: daunorubicin, adriamycin, Ara- C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, PKC412, 6- mercaptopurine (6-MP), fludarabine phosphate, octreotide, SOM230, FTY720, 6- thioguanine, cladribine, 6-mercaptopurine, pentostatin, hydroxyurea, 2-hydroxy-1H- isoindole-1, 3-dione derivatives, l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, l-(4-chloroanilino)-4-(4- pyridylmethyl)phthalazine succinate, angiostatin, end
- second therapeutic agents include, but are not limited to: a treatment for Alzheimer's Disease, such as donepezil and rivastigmine, a treatment for Parkinson's Disease, such as L- DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; an agent for treating multiple sclerosis (MS) such as beta interferon (e.g., AVONEX® and REBIF®), glatiramer acetate, and mitoxantrone; a treatment for asthma, such as albuterol and montelukast; an agent for treating schizophrenia, such as zyprexa, risperdal, seroquel, and haloperidol; an anti-inflammatory agent, such as a corticosteroid, a TNF blocker, IL-1 RA, aza
- the second therapeutically active agent is an immune checkpoint inhibitor.
- immune checkpoint inhibitors include PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG3 inhibitors, TIM3 inhibitors, cd47 inhibitors, and B7-H1 inhibitors.
- islatravir is administered in combination with an immune checkpoint inhibitor is selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a TIM3 inhibitor, and a cd47 inhibitor,
- the immune checkpoint inhibitor is a programmed cell death (PD-1) inhibitor.
- PD-1 is a T-cell coinhibitory receptor that plays a pivotal role in the ability of tumor cells to evade the host's immune system. Blockage of interactions between PD-1 and PD-LI, a ligand of PD-1, enhances immune function and mediates antitumor activity.
- PD-1 inhibitors include antibodies that specifically bind to PD-1. Particular anti-PD-1 antibodies include, but are not limited to nivolumab, pembrolizumab, STI-A1014, and pidilzumab.
- the immune checkpoint inhibitor is a PD-LI (also known as B7-H1 or CD274) inhibitor.
- PD-LI inhibitors include antibodies that specifically bind to PD-LI.
- Particular anti-PD-L1 antibodies include, but are not limited to, avelumab, atezolizumab, durvalumab, and BMS-936559.
- the immune checkpoint inhibitor is a CTLA-4 inhibitor.
- CTLA-4 also known as cytotoxic T-lymphocyte antigen 4
- CTLA-4 is a protein receptor that downregulates the immune system.
- CTLA-4 is characterized as a "brake” that binds costimulatory molecules on antigen-presenting cells, which prevents interaction with CD28 on T cells and also generates an overtly inhibitory signal that constrains T cell activation.
- CTLA-4 inhibitors include antibodies that specifically bind to CTLA-4.
- Particular anti-CTLA-4 antibodies include, but are not limited to, ipilimumab and tremelimumab.
- the immune checkpoint inhibitor is a LAG3 inhibitor.
- LAG3, Lymphocyte Activation Gene 3 is a negative co-simulatory receptor that modulates T cell homeostatis, proliferation, and activation.
- LAG3 has been reported to participate in regulatory T cells (Tregs) suppressive function. A large proportion of LAG3 molecules are retained in the cell close to the microtubule-organizing center, and only induced following antigen specific T cell activation.
- Regs regulatory T cells
- Examples of LAG3 inhibitors include antibodies that specifically bind to LAG3. Particular anti-LAG3 antibodies include, but are not limited to, GSK2831781.
- the immune checkpoint inhibitor is a TIM3 inhibitor.
- TIM3, T-cell immunoglobulin and mucin domain 3 is an immune checkpoint receptor that, functions to limit the duration and magnitude of T H 1 and T C 1 T-cell responses.
- the TIM3 pathway is considered a target for anticancer immunotherapy due to its expression on dysfunctional CD8 + T cells and Tregs, which are two reported immune cell populations that constitute immunosuppression in tumor tissue. Anderson, Cancer Immunology’ Research 2:393-98 (2014).
- Examples of TIM3 inhibitors include antibodies that specifically bind to TIM3.
- the immune checkpoint inhibitor is a cd47 inhibitor. See Unanue, E.R., PNAS 110: 10886-87 (2013).
- antibody is meant to include intact monoclonal antibodies, polyclonal antibodies, multi specific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.
- antibody is meant to include soluble receptors that do not possess the Fc portion of the antibody.
- the antibodies are humanized monoclonal antibodies and fragments thereof made by means of recombinant genetic engineering.
- Another class of immune checkpoint inhibitors include polypeptides that bind to and block PD-1 receptors on T-cells without triggering inhibitor signal transduction.
- Such peptides include B7-DC polypeptides, B7-H1 polypeptides, B7-1 polypeptides and B7-2 polypeptides, and soluble fragments thereof, as disclosed in U.S. Pat. 8,114,845.
- Another class of immune checkpoint inhibitors include compounds with peptide moieties that inhibit PD-1 signaling. Examples of such compounds are disclosed in U.S. Pat. 8,907,053.
- Another class of immune checkpoint inhibitors include inhibitors of certain metabolic enzymes, such as indoleamine 2,3 dioxygenase (IDO), which is expressed by infiltrating myeloid cells and tumor cells.
- IDO indoleamine 2,3 dioxygenase
- the 11)0 enzyme inhibits immune responses by depleting amino acids that are necessary for anabolic functions in T cells or through the synthesis of particular natural ligands for cytosolic receptors that are able to alter lymphocyte functions.
- IDO blocking agents include, but are not limited to levo- 1 -methyl typtophan (L-1MT) and 1 -methyl -tryptophan (1MT).
- the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, STI-Al l 10, avelumab, atezolizumab, durvalumab, STI-A1014, ipilimumab, tremelimumab, GSK2831781, BMS-936559 or MED14736.
- the RTI when the RTI is an FDA approved drug, the RTI may be administered in therapeutically effective amounts that are approved for therapeutic use.
- the amounts effective can be determined with no more than routine experimentation. For example, amounts effective may range from about 1 ng/kg to about 200 mg/kg, about 1 ⁇ g/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg.
- the dosage of a composition can be at any dosage including, but not limited to, about 1 ⁇ g/kg.
- the dosage of a composition may be at any dosage including, but not limited to, about 1 ⁇ g/kg, about 10 ⁇ g/kg, about 25 ⁇ g/kg, about 50 ⁇ g/kg, about 75 ⁇ g/kg, about 100 ⁇ g/kg, about 125 ⁇ g/kg, about 150 ⁇ g/kg, about 175 ⁇ g/kg, about 200 ⁇ g/kg, about 225 ⁇ g/kg, about 250 ⁇ g/kg, about 275 ⁇ g/kg, about 300 ⁇ g/kg, about 325 , ⁇ g/kg, about 350 ⁇ g/kg, about 375 ⁇ g/kg, about 400 ⁇ g/kg, about 425 ⁇ g/kg, about 450 ⁇ g/kg, about 475 ⁇ g/kg, about 500 ⁇ g/kg, about 525 ⁇ g/kg, about 550 ⁇ g/kg, about 575 ⁇ g/kg, about 600 ⁇ g/kg, about 625 ⁇ g/kg, about 650 ⁇
- the dosage is 1 mg-500 mg. In some embodiments, the dosage is 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 mg. These doses may be unitary or divided and may be administered one or more times per day. The above dosages are exemplary of the average case, but there can be individual instances in which higher or lower dosages are merited, and such are within the scope of this disclosure. In practice, the physician determines therapeutically effective amounts and the actual dosing regimen that is most suitable for an individual subject, which can vary with the age, weight, and response of the particular subject.
- the RTI may be administered once, twice or three times per day for 1 day to the end of life, or for 1 day to 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more years, or until the RTI causes unacceptable side effects or is no longer useful.
- the at least one second therapeutic agent is Soltamox® (tamoxifen), Arimidex® (anastrozole), Femara® (letrozole), Aromasin® (exemestane), Herceptin® (trastuzumab), Abraxane® (paclitaxel), Cytoxan® (cyclophosphamide), Taxol® (paclitaxel), Afmitor® (everolimus), Taxotere® (docetaxel), Xeloda® (capeci tabine), Trexall® (methotrexate), Faslodex (fulvestrant), Adriamycin® (doxorubicin), Peijeta® (pertuzumab), Gemzar (gemcitabine), Tykerb® (lapatinib), Adrucil® (fluorouracil), Ibrance® (palbociclib), Verzenio® (abemacic
- the at least one second therapeutic agent is Xeloda® (capecitabine), Eloxatin® (oxaliplatin), fluorouracil, Avastin® (bevacizumab), leucovorin, Camptosar® (irinotecan), Stivarga® (regorafenib), Erbitux® (cetuximab), Vectibix® (panitumumab), Lonsurf® (tipiracil/trifluridine), Zaltrap® (ziv-aflibercept), Betaseron® (interferon beta-lb), Fusilev® (levoleucovorin), Wellcocorin® (methotrexate), Keytruda® (pembrolizumab), Mvasi® (bevacizumab-awwb), Cyramza® (ramucirumab), Yervoy® (ipilmum
- the at least one second therapeutic agent is Etopophos® (etoposide), Hycamtin® (topotecan), VePesid® (etoposide), Toposar® (etoposide), Opdivo® (nivolumab), Keytruda® (pembrolizumab), Tecentriq® (atezolizumab), Imfmizi® (durvalumab), methotrexate, cyclophosphamide, Carboplatin, Cisplatin, docetaxel, Gemcitabine, Irinotecan, Paclitaxel, Pemetrexed, Vinblastine, or Vinorelbine.
- Etopophos® etoposide
- Hycamtin® topotecan
- VePesid® etoposide
- Toposar® etoposide
- Opdivo® nivolumab
- Keytruda® pembrolizumab
- Tecentriq® atezolizum
- the at least one second therapeutic agent is Gemzar® (Gemcitabine), fluorouracil, Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (irinotecan), bevacizumab, cetuximab, Infugem® (gemcitabine) or Lynparza® (olaparib).
- Gemzar® Gamcitabine
- fluorouracil Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (
- the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
- the at least one second therapeutic agent is Suprefact® (buserelin), Firmagon® (degarelix), Zoladex® (goserelin), Vanias® (histrelin), Eligard® (leuprolide), Orgovyx® (relugolix), Trelstar® (triptorelin), Casodex® (bicalutamide), Eulexin® (flutamide), Nilandron® (nilutamide), Zytiga® (biraterone acetate), Erleada® (apalutamide), or Xtandi ® (enzal utami de) .
- the at least one second therapeutic agent is a STING agonist.
- STING agonists include E7766, MIW815, SNX281, and TAK-676. See, e.g., Aval et al., Journal of Clinical Medicine 9:3323 (2020); Su et al., Theranostics 9:7759- 7771 (2019).
- the RTI and/or DDR enzyme inhibitor and at least one second therapeutic agent may be administered separately or together as part of a unitary pharmaceutical composition.
- the patient is (a) not infected with the HIV virus, (b) not suspected of being infected with the HIV virus, (c) not being treated for the HIV virus, and/or (d) not being treated to prevent the HIV virus.
- patient and “subject” as used herein are synonymous terms referring to any human or animal that is in need of or might benefit from administration of a RTI and/or DDR enzyme inhibitor for treating cancer.
- mammals e.g., humans, although the methods and compositions provided herein are not intended to be so limited.
- Other subjects include veterinary animals, e.g., cows, sheep, pigs, horses, dogs, cats and the like.
- the subject is a human.
- the subject is an animal.
- the methods of the present disclosure can be accomplished by administering RTI as the neat compound or as a pharmaceutical composition.
- Administration of a pharmaceutical composition, or a neat RTI and/or DDR enzyme inhibitor can be performed before, during, or after the clinical diagnosis of the cancer.
- the pharmaceutical compositions are sterile, and contain no toxic, carcinogenic, or mutagenic compounds that would cause an adverse reaction when administered.
- kits comprising the RTI and/or DDR enzyme inhibitor and, optionally, at least one second therapeutic agent useful for the treatment of cancer associated, packaged separately or together, and an insert having instructions for using these active agents.
- the RTI and/or DDR enzyme inhibitor is packaged alone together with instructions to administered together with the at least one second therapeutic agent.
- the RTI and/or DDR enzyme inhibitor and the at least one second therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect.
- the RTI and the at least one second therapeutic agent can be administered from a single composition or two separate compositions.
- the second therapeutic agent is administered in an amount to provide its desired therapeutic effect.
- the effective dosage range for each optional therapeutic agent is known in the art, and the optional therapeutic agent is administered to an individual in need thereof within such established ranges.
- the present disclosure encompasses the preparation and use of salts of a RTI and/or DDR enzyme inhibitor.
- a "pharmaceutically acceptable salt” refers to salts or zwitterionic forms of a RTI and/or DDR enzyme inhibitor. Salts of a RTI and/or DDR enzyme inhibitor can be prepared during the final isolation and purification of the compound or separately by reacting the compound with a suitable acid.
- the pharmaceutically acceptable salts of a RTI and/or DDR enzyme inhibitor can be acid addition salts formed with pharmaceutically acceptable acids.
- acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
- Non-limiting examples of salts of a RTI and/or DDR enzyme inhibitor include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerol phsphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesityl enesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulf
- solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents.
- solvate as used herein is a combination, physical association and/or solvation of a compound with a solvent molecule such as, e.g. a - disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound is about 2: 1, about 1 : 1 or about 1 :2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding.
- solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
- solvate encompasses both solution- phase and isolatable solvates.
- a RTI and/or DDR enzyme inhibitor can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, and ethanol. It is intended that the disclosure includes both solvated and unsolvated forms of a RTI.
- solvate is a hydrate.
- a "hydrate” relates to a particular subgroup of solvates where the solvent molecule is water.
- Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M.
- a typical, non-limiting, process of preparing a solvate would involve dissolving a RTI in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration.
- Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvate in a cry sial of the solvate.
- the RTI and/or DDR enzyme inhibitor is typically are administered in admixture with a pharmaceutical carrier to give a pharmaceutical composition selected with regard to the intended route of administration and standard pharmaceutical practice.
- Pharmaceutical compositions for use in accordance with the present disclosure are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the RTI and/or DDR enzyme inhibitor.
- compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen.
- a therapeutically effective amount of a RTI and/or DDR enzyme inhibitor is administered orally, the composition typically is in the form of a tablet, capsule, powder, solution, or elixir.
- the composition additionally can contain a solid carrier, such as a gelatin or an adjuvant.
- the tablet, capsule, and powder contain about 0.01% to about 95%, and preferably from about 1% to about 50%, of a RTI and/or DDR enzyme inhibitor, or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof.
- a liquid carrier such as water, petroleum, or oils of animal or plant origin, can be added.
- the liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solutions, or glycols.
- the composition contains about 0.1 % to about 90%, and preferably about 1% to about 50%, by weight, of a RTI and/or DDR enzyme inhibitor.
- composition When a therapeutically effective amount of a RTI and/or DDR enzyme inhibitor is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution.
- parenterally acceptable solutions having due regard to pH, isotonicity, stability, and the like, is within the skill in the art.
- a preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains, an isotonic vehicle.
- a RTI and/or DDR enzyme inhibitor can be readily combined with pharmaceutically acceptable carriers well-known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995. Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
- Pharmaceutical preparations for oral use can be obtained by adding a RTI and/or DDR enzyme inhibitor to a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrating agents can be added.
- a RTI and/or DDR enzyme inhibitor can be formulated for parenteral administration by injection, e.g,, by bolus injection or continuous infusion.
- Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative.
- the compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.
- compositions for parenteral administration include aqueous solutions of the RTI and/or DDR enzyme inhibitor in water-soluble form.
- suspensions of a compound of a RTI can be prepared as appropriate oily injection suspensions.
- Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters.
- Aqueous injection suspensions can contain substances which increase the viscosity of the suspension.
- the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions.
- a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
- a RTI and/or DDR enzyme inhibitor can be administered orally in the form of tablets containing excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
- excipients such as starch or lactose
- capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
- Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents.
- a RTI and/or DDR enzyme inhibitor also can be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily.
- a RTI and/or DDR enzyme inhibitor typically used in the form of a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.
- biomarker refers to any biological compound, such as a gene, a protein, a fragment of a protein, a peptide, a polypeptide, a nucleic acid, etc., or chromosome abnormality, such as a chromosome translocation, that can be detected and/or quantified in a subject in vivo or in a biological sample obtained from a subject.
- a biomarker can be the entire intact molecule, or it can be a portion or fragment thereof.
- the expression level of the biomarker is measured.
- the expression level of the biomarker can be measured, for example, by detecting the protein or RNA, e.g., mRNA, level of the biomarker.
- portions or fragments of biomarkers can be detected or measured, for example, by an antibody or other specific binding agent.
- a measurable aspect of the biomarker is associated with a given state of the subject, such as the subject's age.
- measurable aspects may include, for example, the presence, absence, or concentration, i.e., expression level, of the biomarker in the subject, or biological sample obtained from the subject.
- measurable aspects may include, for example, allelic versions of the biomarker or type, rate, and/or degree of mutation of the biomarker, also referred to herein as mutation status.
- biomarkers that are detected based on expression level of protein or RNA expression level measured between different phenotypic statuses can be considered different, for example, if the mean or median expression level of the biomarker in the different groups is calculated to be statistically significant. Common tests for statistical significance include, among others, t-test, ANOVA, Kruskal -Wall is, Wilcoxon, Mann- Whitney, Significance Analysis of Microarrays, odds ratio, etc.
- Biomarkers, alone or in combination provide measures of relative likelihood that a subject belongs to one phenotypic status or another. Therefore, they are useful, inter alia, as markers for disease and as indicators that particular therapeutic treatment regimens will likely result in beneficial patient outcomes.
- overexpression indicates that the expression level of the biomarker in the subject having a disease, condition, or disorder is amplified, e.g., above the mean or median expression level of the biomarker in, e.g., a normal undiseased subject.
- Biomarkers include, but are not limited to, DDR enzymes, e.g., Pol ⁇ Pol ⁇ , or Pol ⁇ , or genes, e.g., POLE, POLM, or POLQ.
- the measurable aspect of the biomarker is its expression status.
- the measurable aspect of the biomarker is elevated levels, e.g., over express! on, of the biomarker.
- the measurable aspect of the biomarker is its mutation status.
- the biomarker is Pol ⁇ expression which is differentially present in a subject of one phenotypic status, e.g., a subject having cancer as compared with another phenotypic status, e.g., a normal undiseased subject or a subject having a cancer without overexpression of Pol ⁇ .
- the biomarker is overexpression of Pol ⁇ in cancer cells.
- the biomarker is Pol ⁇ expression which is differentially present in a subject of one phenotypic status, as compared with another phenotypic status.
- the biomarker is overexpression of Pol ⁇ , e.g., in cancer cells.
- the biomarker is overexpression of POLE, e.g., in cancer cells.
- the biomarker is Pol ⁇ expression which is differentially present in a subject of one phenotypic status as compared with another phenotypic status.
- the biomarker is overexpression of Pol ⁇ , e.g., in cancer cells.
- the biomarker is overexpression of POLM, e.g., in cancer cells.
- the biomarker is BR.CA1 expression which is differentially present in a subject of one phenotypic status, e.g., a subject having cancer as compared with another phenotypic status, e.g., a normal undiseased subject or a subject having a cancer without overexpression of BRCA1 .
- the biomarker is overexpression of BRCA1 in cancer cells.
- the biomarker is BRCA2 expression which is differentially present in a subject of one phenotypic status, e.g., a subject having cancer as compared with another phenotypic status, e.g., a normal undiseased subject or a subject having a cancer without overexpression of BRCA2.
- the biomarker is overexpression of BRCAl in cancer cells.
- the biomarker is Pol ⁇ , Pol ⁇ or Pol ⁇ expression which is differentially present in a subject of one phenotypic status, e.g., a subject after administration of a Compound of the Disclosure, as compared with another phenotypic status, e.g., a normal undiseased subject or a subject before administration of a Compound of the Disclosure.
- the biomarker is descressed expression of Pol ⁇ , Pol ⁇ , or Pol ⁇ caused by administration of a Compound of the Disclosure to a subject.
- Biomarker standards can be predetermined, determined concurrently, or determined after a biological sample is obtained from the subject.
- Biomarker standards for use with the methods described herein can, for example, include data from samples from subjects without cancer and/or data from samples from subjects with a cancer. Comparisons can be made to establish predetermined threshold biomarker standards for different classes of subjects, e.g., diseased vs. non-diseased subjects. The standards can be run in the same assay or can be known standards from a previous assay.
- a biomarker is differentially present between different phenotypic status groups if the mean or median expression or mutation levels of the biomarker is calculated to be different, i.e., higher or lower, between the groups.
- biomarkers provide an indication that a subject, e.g., a subject having cancer, belongs to one phenotypic status or another.
- biomarker in addition to individual biological compounds, e.g., Pol ⁇ , the term “biomarker” as used herein is meant to include groups, sets, or arrays of multiple biological compounds.
- biomarker may comprise one, two, three, four, five, six, seven, eight, nine, ten, fifteen, twenty, twenty five, thirty, or more, biological compounds.
- the biomarker comprises one, two, or three biological compounds.
- the determination of the expression level or mutation status of a biomarker in a subject can be performed using any of the many methods known in the art. Any method known in the art for quantitating specific proteins and/or detecting biomarker expression, e.g., Pol ⁇ , Pol ⁇ , or Pol ⁇ expression, and/or or the expression or mutation levels of any other biomarker(s) in a patient or a biological sample may be used in the methods of the disclosure. Examples include, but are not limited to, PCR (polymerase chain reaction), or RT-PCR, flow cytometry.
- RNA expression e.g., ELISA (enzyme linked immunosorbent assay), RIA (radioimmunoassay), Simoa TM , gene chip analysis of RNA expression, immunohistochemistry, immunofluorescence, or massspectroscopy.
- ELISA enzyme linked immunosorbent assay
- RIA radioimmunoassay
- Simoa TM gene chip analysis of RNA expression, immunohistochemistry, immunofluorescence, or massspectroscopy.
- Certain embodiments of the disclosure include methods wherein biomarker RNA expression (transcription) is determined.
- Other embodiments of the disclosure include methods wherein protein expression in the biological sample is determined.
- a biological sample is obtained from the subject and the biological sample is assayed for determination of a biomarker expression or mutation status.
- the biological sample is blood from the subject.
- the biological sampl e is the cancer tissue or cells of the patient,
- Northern blot analysis of biomarker transcription in a tumor cell sample is performed.
- Northern analysis is a standard method for detection and/or quantitation of mRNA levels in a sample. Initially, RNA is isolated from a sample to be assayed using Northern biot analysis, In the analysis, the RNA samples are first separated by size via electrophoresis in an agarose gel under denaturing conditions. The RNA is then transferred to a membrane, crosslinked and hybridized with a labeled probe. Typically, Northern hybridization involves polymerizing radiolabeled or nonisotopically labeled DNA, in vitro, or generation of oligonucleotides as hybridization probes.
- the membrane holding the RNA sample is prehybridized or blocked prior to probe hybridization to prevent the probe from coating the membrane and, thus, to reduce non-specific background signal.
- unhybridized probe is removed by washing in several changes of buffer. Stringency of the wash and hybridization conditions can be designed, selected and implemented by any practitioner of ordinary skill in the art. Detection is accomplished using detectably labeled probes and a suitable detection method. Radiolabeled and non-radiolabled probes and their use are well known in the art. The presence and or relative levels of expression of the biomarker being assayed can be quantified using, for example, densitometry.
- biomarker expression and/or mutation status is determined using RT-PCR.
- RT-PCR allows detection of the progress of a PCR amplification of a target gene in real time. Design of the primers and probes required to detect expression and/or mutation status of a biomarker of the disclosure is within the skill of a practitioner of ordinary skill in the art..
- RT-PCR can be used, for example, to determine the level of RNA encoding a biomarker of the disclosure in a tissue sample.
- RNA from the biological sample is isolated, under RNAse free conditions, than converted to DNA by treatment with reverse transcriptase. Methods for reverse transcriptase conversion of RNA to DNA are well known in the art..
- RT-PCR probes depend on the 5'-3‘ nuclease activity of the DNA polymerase used for PCR to hydrolyze an oligonucleotide that is hybridized to the target amplicon (biomarker gene).
- RT-PCR probes are oligonucleotides that have a fluorescent reporter dye attached to the 5' end and a quencher moiety coupled to the 3' end (or vice versa). These probes are designed to hybridize to an internal region of a PCR product. In the unhybridized state, the proximity of the fluor and the quench molecules prevents the detection of fluorescent signal from the probe.
- a western blot is a method for protein detection in a given sample of tissue homogenate or extract. It uses gel electrophoresis to separate denatured proteins by mass. The proteins are then transferred out of the gel and onto a membrane (e.g., nitrocellulose or poly vinylidene fluoride (PVDF)), where they are detected using a primary antibody that specifically bind to the protein. The bound antibody can then detected by a secondary' antibody that is conjugated with a detectable label (e.g., biotin, horseradish peroxidase or alkaline phosphatase). Detection of the secondary label signal indicates the presence of the protein.
- a detectable label e.g., biotin, horseradish peroxidase or alkaline phosphatase.
- the expression of a protein encoded by a biomarker is detected by enzyme-linked immunosorbent assay (ELISA).
- ELISA enzyme-linked immunosorbent assay
- "sandwich ELISA” comprises coating a plate with a capture antibody; adding sample wherein any antigen present binds to the capture antibody; adding a detecting antibody which also binds the antigen, adding an enzyme-linked secondary antibody which binds to detecting antibody; and adding substrate which is converted by an enzyme on the secondary antibody to a detectable form. Detection of the signal from the secondary antibody indicates presence of the biomarker antigen protein.
- present disclosure provides methods of treating a subject having cancer, the method comprising: (a) determining whether a biomarker, e.g., overexpression of Pol ⁇ , Pol ⁇ , or Pol ⁇ , is present or absent in a biological sample taken from the subject; and (b) administering an RTI and/or DDR enzyme inhibitor to the subject if the biomarker is present in the biological sample.
- a biomarker e.g., overexpression of Pol ⁇ , Pol ⁇ , or Pol ⁇
- the present disclosure provides a method of identifying whether a subject having cancer as a candidate for treatment with a RTI and/or DDR enzyme inhibitor, the method comprising: (a) determining whether a biomarker, e.g.. overexpression of POLQ, is present or absent in a biological sample taken from the subject; and (b) identifying the subject as being a candidate for treatment if the biomarker is present; or (c) identifying the subject as not being a candidate for treatment if the biomarker is absent.
- a biomarker e.g.. overexpression of POLQ
- the present disclosure provides a method of predicting treatment outcome in a subject having cancer, the method comprising determining whether a bi ⁇ marker, e.g., overexpression of Pol ⁇ , Pol rp or Pol ⁇ , is present or absent in a biological sample taken from the subject, wherein (a) the presence of the biomarker in the biological sample indicates that administering a RTI and/or DDR enzyme inhibitor to the subject will likely cause a favorable therapeutic response; and (b) the absence of the biomarker in the biological sample indicates that administering a RTI and/or DDR enzyme inhibitor to the subject will likely cause an unfavorable therapeutic response.
- a bi ⁇ marker e.g., overexpression of Pol ⁇ , Pol rp or Pol ⁇
- the present disclosure provides a method, comprising administering a therapeutically effective amount of a RTI and/or DDR enzyme inhibitor to a subject in need thereof, wherein: (a) the subject has cancer; and (b) the cancer is characterized as having a biomarker, e.g., overexpression of one or more DNA damage repair enzymes, e.g., overexpression of Pol 6, Pol ⁇ , or Pol ⁇ .
- a biomarker e.g., overexpression of one or more DNA damage repair enzymes, e.g., overexpression of Pol 6, Pol ⁇ , or Pol ⁇ .
- the present disclosure provides a method of treating a subject having cancer, the method comprising:
- the present disclosure provides a method of identifying whether a subject having cancer as a candidate for treatment with a Compound of the Disclosure, the method comprising:
- the present disclosure provides a method of predicting treatment outcome in a subject having cancer, the method comprising determining whether an overexpression of one or more DNA damage repair enzymes, e.g., Pol ⁇ , Pol ⁇ , and/or Pol ⁇ , is present or absent in a biological sample taken from the subject, wherein:
- the present disclosure provides a Compound of the Disclosure for use in treating a subject having cancer, wherein;
- a biomarker e.g., one or more DNA damage repair enzymes, e.g., Pol 6, Pol ⁇ , and/or Pol ⁇ , in a biological sample taken from the subject is determined; and
- the present disclosure provides the use of a Compound of the Disclosure in the manufacture of a medicament for treating a subject having cancer, wherein:
- a biomarker e.g., one or more DNA damage repair enzymes, e.g., Pol ⁇ , Pol ⁇ and/or Pol ⁇
- a biomarker e.g., one or more DNA damage repair enzymes, e.g., Pol ⁇ , Pol ⁇ and/or Pol ⁇
- A DNA damage repair enzyme inhibitors for treating cancer.
- Embodiment 1 A method for treating cancer in subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Table 3 to the subject.
- Embodiment 2 The method of Embodiment 1, wherein the compound of Table 3 is 2-amino-9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-
- Embodiment 3 The method of Embodiment 1, wherein the compound of Table 3 is (2R,3 S,5R)-5-(4-amino-2-oxopyrimidin- 1 (2H)-yl)-3-hydroxy-2-
- Embodiment 4 The method of Embodiment 1, wherein the compound of Table 3 is (2R,3S,5R)-5-(2,6-diamino-9H-purin-9-yl)-2-(hydroxymethyl)-2- vinyltetrahydrofuran-3-ol; (2R,3S,5R)-5-(2,6-di amino- 9H-purin-9-yl)-2-ethyl-2-
- Embodiment 5 The method of any one of Embodiments 1-4, wh erein the cancer is breast cancer, colon cancer, lung cancer, pancreatic ductal cancer, prostate cancer, ovarian cancer, or head and neck cancer.
- Embodiment 6 The method of Embodiment 5, wherein the cancer is breast cancer.
- Embodiment 7 The method of Embodiment 5, wherein the cancer is colon cancer.
- Embodiment 8 The method of Embodiment 5, wherein the cancer is lung cancer.
- Embodiment 9 The method of Embodiment 5, wherein the cancer is pancreatic ductal cancer.
- Embodiment 10 The method of Embodiment 5, wherein the cancer is prostate cancer.
- Embodiment 11 The method of Embodiment 5, wherein the prostate cancer is high-risk localized prostate cancer.
- Embodiment 12 The method of Embodiment 5, wherein the cancer is ovarian cancer.
- Embodiment 13 The method of Embodiment 5, wherein the cancer is head and neck cancer.
- Embodiment 14 The method of any one of Embodiments 1-5, wherein the subject has prostate cancer and the compound of Table 3 is administered as an adjuvant therapy.
- Embodiment 15 The method of any one of Embodiments 1-5, wherein the subject has prostate cancer and the compound of Table 3 is administered as a neoadjuvant therapy.
- Embodiment 16 The method of any one of Embodiments 1-15 further comprising administering a therapeutically effective amount of at least one second therapeutic agent useful for treating the cancer.
- Embodiment 17 The method of Embodiment 16, wherein the cancer is breast cancer and the at least one second therapeutic agent is Soltamox® (tamoxifen), Arimidex® (anastrozole), Femara® (letrozole), Aromasin® (exemestane), Herceptin® (trastuzumab), Abraxane® (paclitaxel), Cytoxan® (cyclophosphamide), Taxol® (paclitaxel), Afinitor® (everolimus), Taxotere® (docetaxel), Xeloda® (capecitabine), Trexall® (methotrexate), Faslodex (fulvestrant), Adriamycin® (doxorubicin), Perjeta® (pertuzumab), Gemzar (gemcitabine), Tykerb® (lapatinib), Adrucil® (fluorouracil), Ibrance® (palbociclib), Verzenio® (abemaciclib),
- Embodiment 18 The method of Embodiment 16, wherein the cancer is colon cancer and the at least one second therapeutic agent is Xeloda® (capeci tabine), El oxatin® (oxaliplatin), fluorouracil, A vastin® (bevacizumab), leucovorin, Camptosar® (irinotecan), Stivarga® (regorafenib), Erbitux® (cetuximab), Vectibix® (panitumumab), Lonsurf® (tipiracil/trifluridine), Zaltrap® (ziv-aflibercept), Betaseron® (interferon beta- lb), Fusilev® (levoleucovorin), Wellcocorin® (methotrexate), Keytruda® (pembrolizumab), Mvasi® (bevacizumab-awwb), Cyramza® (ramucirumab), Yervoy®
- Embodiment 19 The method of Embodiment 16, wherein the cancer is lung cancer and the at least one second therapeutic agent is Etopophos® (etoposide), Hycamtin® (topotecan), VePesid® (etoposide), Toposar® (etoposide), Opdivo® (nivolumab), Keytruda® (pembrolizumab), Tecentriq® (atezolizumab), Imfinizi® (durvalumab), methotrexate, cyclophosphamide, Carboplatin, Cisplatin, docetaxel, Gemcitabine, Irinotecan, Paclitaxel, Pemetrexed, Vinblastine, or Vinorelbine.
- Etopophos® etoposide
- Hycamtin® topotecan
- VePesid® etoposide
- Toposar® etoposide
- Opdivo® nivolumab
- Embodiment 20 The method of Embodiment 16, wherein the cancer is pancreatic ductal cancer and the at least one second therapeutic agent is Gemzar® (Gemcitabine), fluorouracil, Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (irinotecan), bevacizumab, cetuximab, Infugem® (gemcitabine) or Lynparza® (olaparib).
- Gemzar® Gamcitabine
- fluorouracil Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar
- Embodiment 21 The method of Embodiment 16, wherein the cancer is head and neck cancer and the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
- Erbituz® cetuximab
- Taxotere® docetaxel
- Trexall® metalhotrexate
- Keytruda® pembrolizumab
- Opdivo® nivolumab
- Embodiment 22 The method of Embodiment 16, wherein the cancer is prostate cancer and the at least one second therapeutic agent is Suprefact® (buserelin), Firmagon® (degarelix), Zoladex® (goserelin), Vantas® (histrelin), Eligard® (leuprolide), Orgovyx® (relugolix), Trelstar® (triptorelin), Casodex® (bicalutamide), Eulexin® (flutamide), Nilandron® (nilutamide), Zytiga® (biraterone acetate), Erleada® (apalutamide), or Xtandi® (enzalutamide).
- Suprefact® buserelin
- Firmagon® degarelix
- Zoladex® goserelin
- Vantas® histrelin
- Eligard® leuprolide
- Orgovyx® relugolix
- Trelstar® triptorelin
- Embodiment 23 The method of Embodiment 16, wherein the at least one second therapeutic agent is a STING agonist.
- Embodiment 24 The method of any one of Embodiments 1-23, wherein the subject is (a) not infected with the HIV virus, (b) not suspected of being infected with the HIV virus, (c) not being treated for the HIV virus, and/or (d) not being treated to prevent the HIV virus.
- Embodiment 25 A kit for carrying out the method of any one Embodiments 1-24, the kit comprising (i) a compound of Table 3; and (ii) and instructions for administering the compound of Table 3 to a subject having cancer.
- Embodiment 26 The kit of Embodiment 25 further comprising at least one second therapeutic agent.
- Embodiment 27 The method of any one of Embodiments 1-24, wherein the cells of the cancer are suspected to or exhibit deficiency of a DDR enzyme, e.g., one or more DDR enzymes of Table C, e.g., Pol ⁇ , Pol ⁇ , and/or Pol ⁇ , or the cells of the cancer are suspected to or exhibit amplification of a DDR gene, e.g., one or more DDR genes of Table C, e.g., POLE, POLM, and/or POLQ.
- a DDR enzyme e.g., one or more DDR enzymes of Table C, e.g., Pol ⁇ , Pol ⁇ , and/or Pol ⁇
- a DDR gene e.g., one or more DDR genes of Table C, e.g., POLE, POLM, and/or POLQ.
- Embodiment 1 A compound of Table 3 for use in treating cancer in a subj ect.
- Embodiment 2 The compound of Table 3 for use of Embodiment 1, wherein the compound of Table 3 is 2-amino-9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-1 ,9-dihydro-6H-purin-6-one; 4-amino-1-
- Embodiment 3 The compound of Table 3 for use of Embodiment 1 , wherein the compound of Table 3 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-hydroxy- 2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile; 4-amino-1-((2R,4S,5R)-4-hydroxy ⁇ 5- (hydroxymethyl)-5-methyltetrahydrofuran-2-yl)pyrimidin-2(1H)-one; or 4-amino-1- ((2R,4S,5R)-5-ethyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)- one.
- Embodiment 4 The compound of Table 3 for use of Embodiment 1, wherein the compound of Table 3 is (2R,3S,5R)-5-(2,6-diamino-9H-purin-9-y
- Embodiment 5 The compound of Table 3 for use of any one of Embodiments
- cancer is breast cancer, colon cancer, lung cancer, pancreatic ductal cancer, prostate cancer, ovarian cancer, or head and neck cancer.
- Embodiment 6 The compound of Table 3 for use of Embodiment 5, wherein the cancer is breast cancer.
- Embodiment 7 The compound of Table 3 for use of Embodiment 5, wherein the cancer is colon cancer.
- Embodiment 8 The compound of Table 3 for use of Embodiment 5, wherein the cancer is lung cancer.
- Embodiment 9 The compound of Table 3 for use of Embodiment 5, wherein the cancer is pancreatic ductal cancer.
- Embodiment 10 The compound of Table 3 for use of Embodiment 5, wherein the cancer is prostate cancer.
- Embodiment 11 The compound of Table 3 for use of Embodiment 5, wherein the prostate cancer is high-risk localized prostate cancer.
- Embodiment 12 The compound of Table 3 for use of Embodiment 5, wherein the cancer is ovarian cancer.
- Embodiment. 13 The compound of "fable 3 for use of Embodiment 5, wherein the cancer is head and neck cancer.
- Embodiment 14 The compound of Table 3 for use of any one of Embodiments
- Embodiment 15 The compound of Table 3 for use of any one of Embodiments
- Embodiment 16 The compound of Table 3 for use of any one of Embodiments
- 1-15 further comprising administering a therapeutically effective amount of at least one second therapeutic agent useful for treating the cancer.
- Embodiment 17 The compound of Table 3 for use of Embodiment 16, wherein the cancer is breast cancer and the at least one second therapeutic agent is Soltamox® (tamoxifen), Arimidex® (anastrozole), Femara® (letrozole), Aromasin® (exemestane), Herceptin® (trastuzumab), Abraxane® (paclitaxel), Cytoxan® (cyclophosphamide), Taxol® (paclitaxel), Afinitor® (everolimus), Taxotere® (docetaxel), Xeloda® (capecitabine), Trexall® (methotrexate), Faslodex (fulvestrant), Adriamycin® (doxorubicin), Perjeta® (pertuzumab), Gemzar (gemcitabine), Tykerb® (lapatinib), Adrucil® (fluorouracil), Ibrance® (palbociclib), Verzenio® (a
- Embodiment 18 The compound of Table 3 for use of Embodiment 16, wherein the cancer is colon cancer and the at least one second therapeutic agent is Xeloda® (capecitabine), Eloxatin® (oxaliplatin), fluorouracil, Avastin® (bevacizumab), leucovorin, Camptosar® (irinotecan), Stivarga® (regorafenib), Erbitux® (cetuximab), Vectibix® (panitumumab), Lonsurf® (tipiracil/trifluridine), Zaltrap® (ziv-aflibercept), Betaseron® (interferon beta-lb), Fusilev® (levoleucovorin), Wellcocorin® (methotrexate), Keytruda® (pembrolizumab), Mvasi® (bevacizumab-awwb), Cyramza® (ramucirumab), Yervoy
- Embodiment 19 The compound of Table 3 for use of Embodiment 16, wherein the cancer is lung cancer and the at least one second therapeutic agent is Etopophos® (etoposide), Hycamtin® (topotecan), VePesid® (etoposide), Toposar® (etoposide), Opdivo® (nivolumab), Keytruda® (pembrolizumab), Tecentriq® (atezolizumab), Imfinizi® (durvaiumab), methotrexate, cyclophosphamide, Carboplatin, Cisplatin, docetaxel.
- Gemcitabine Irinotecan, Paclitaxel, Pemetrexed, Vinblastine, or Vinorelbine.
- Embodiment 20 The compound of Table 3 for use of Embodiment 16, wherein the cancer is pancreatic ductal cancer and the at least one second therapeutic agent is Gemzar® (Gemcitabine), fluorouracil, Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (irinotecan), bevacizumab, cetuximab, Infugem® (gemcitabine) or Lynparza® (olaparib).
- Gemzar® Gamcitabine
- fluorouracil Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrex
- Embodiment 21 The compound of Table 3 for use of Embodiment 16, wherein the cancer is head and neck cancer and the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
- Erbituz® cetuximab
- Taxotere® docetaxel
- Trexall® metalhotrexate
- Keytruda® pembrolizumab
- Opdivo® nivolumab
- Embodiment 22 The compound of Table 3 for use of Embodiment 16, wherein the cancer is prostate cancer and the at least one second therapeutic agent is Suprefact® (buserelin), Firmagon® (degarelix), Zoladex® (goserelin), Vantas® (histrelin), Eligard® (leuprolide), Orgovyx® (relugolix), Trelstar® (triptorelin), Casodex® (bicalutamide), Eulexin® (flutamide), Nilandron® (nilutamide), Zytiga® (biraterone acetate), Erleada® (apalutamide), or Xtandi® (enzalutamide).
- Suprefact® buserelin
- Firmagon® degarelix
- Zoladex® goserelin
- Vantas® histrelin
- Eligard® leuprolide
- Orgovyx® relugolix
- Trelstar® triptorelin
- Embodiment 23 The compound of Table 3 for use of Embodiment 16, wherein the at least one second therapeutic agent is a STING agonist.
- Embodiment 24 The compound of Table 3 for use of any one of Embodiments
- the subject is (a) not infected with the HIV virus, (b) not suspected of being infected with the HIV virus, (c) not being treated for the HIV virus, and/or (d) not being treated to prevent the HIV virus.
- Embodiment 25 The compound of Table 3 for use of any one of Embodiments 1-24, wherein the cells of the cancer are suspected to or exhibit deficiency of a DDR enzyme, e.g., one or more DDR enzymes of Table C, e.g., Pol q, Pol ⁇ , and/or Pol ⁇ , or the cells of the cancer are suspected to or exhibit amplification of a DDR gene, e.g., one or more DDR genes of Table C, e.g., POLH, POLM, and/or POLQ.
- a DDR enzyme e.g., one or more DDR enzymes of Table C, e.g., Pol q, Pol ⁇ , and/or Pol ⁇
- the cells of the cancer are suspected to or exhibit amplification of a DDR gene, e.g., one or more DDR genes of Table C, e.g., POLH, POLM, and/or POLQ.
- C DNA damage
- Embodiment 1 Use of a compound of Table 3 in the manufacture of a medicament for treating cancer in a subject.
- Embodiment 2 The use of Embodiment 1, wherein the compound of Table 3 is 2-amino-9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl) ⁇ 1,9-dihydro-6H-purin-6-one; 4-amino-1-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-
- Embodiment 3 The use of Embodiment 1 , wherein the compound of T able 3 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-hydroxy-2-
- Embodiment 4 The use of Embodiment 1, wherein the compound of Table 3 is (2R,3S,5R)”5-(2,6-diamino-9H-purin-9-yl)”2-(hydroxymethyl)-2-vinyltetrahydrofuran- 3-ol; (2R,3S,5R)-5-(2,6-diamino-9H-purin-9-yl)-2-ethyl-2-
- Embodiment 5 The use of any one of Embodiments 1-4, wherein the cancer is breast cancer, colon cancer, lung cancer, pancreatic ductal cancer, prostate cancer, ovarian cancer, or head and neck cancer.
- Embodiment 6 The use of Embodiment 5, wherein the cancer is breast cancer.
- Embodiment 7 The use of Embodiment 5, wherein the cancer is colon cancer.
- Embodiment 8 The use of Embodiment 5, wherein the cancer is lung cancer.
- Embodiment 9 The use of Embodiment 5, wherein the cancer is pancreatic ductal cancer.
- Embodiment 10 The use of Embodiment 5, wherein the cancer is prostate cancer.
- Embodiment 11 The use of Embodiment 5, wherein the prostate cancer is high-risk localized prostate cancer.
- Embodiment 12 The use of Embodiment 5, wherein the cancer is ovarian cancer.
- Embodiment 13 The use of Embodiment 5, wherein the cancer is head and neck cancer.
- Embodiment 14 The use of any one of Embodiments 1-5, wherein the subject has prostate cancer and the compound of Table 3 is administered as an adjuvant therapy.
- Embodiment 15 The use of any one of Embodiments 1-5, wherein the subject has prostate cancer and the compound of Table 3 is administered as a neoadjuvant therapy.
- Embodiment 16 The use of any one of Embodiments 1-15 further comprising administering a therapeutically effective amount of at least one second therapeutic agent useful for treating the cancer.
- Embodiment 17 The use of Embodiment 16, wherein the cancer is breast cancer and the at least one second therapeutic agent is Soltamox® (tamoxifen), Arimidex® (anastrozole), Femara® (letrozole), Aromasin® (exemestane), Herceptin® (trastuzumab), Abraxane® (paclitaxel), Cytoxan® (cyclophosphamide), Taxol® (paclitaxel), Afmitor® (everolimus), Taxotere® (docetaxel), Xeloda® (capecitabine), Trexall® (methotrexate), Faslodex (fulvestrant), Adriamycin® (doxorubicin), Perjeta® (pertuzumab), Gemzar (gemcitabine), Tykerb® (lapatinib), Adrucil® (fluorouracil), Ibrance® (palbociclib), Verzenio® (abemaciclib), Verzen
- Embodiment 18 The use of Embodiment 16, wherein the cancer is colon cancer and the at least one second therapeutic agent is Xeloda® (capecitabine), Eloxatin® (oxaliplatin), fluorouracil, Avastin® (bevacizumab), leucovorin, Camptosar® (irinotecan), Stivarga® (regorafenib), Erbitux® (cetuximab), Vectibix® (panitumumab), Lonsurf® (tipi racil/trifluri dine), Zaltrap® (ziv-aflibercept), Betaseron® (interferon beta-lb), Fusilev® (levoleucovorin), Wellcocorin® (methotrexate), Keytruda® (pembrolizumab), Mvasi® (bevacizumab-awwb), Cyramza® (ramucirumab), Yervoy® (
- Embodiment 19 The use of Embodiment 16, wherein the cancer is lung cancer and the at least one second therapeutic agent is Etopophos® (etoposide), Hycamtin® (topotecan), VePesid® (etoposide), Toposar® (etoposide), Opdivo® (nivolumab), Keytruda® (pembrolizumab), Tecentriq® (atezolizumab), Imfmizi® (durvalumab), methotrexate, cyclophosphamide, Carboplatin, Cisplatin, docetaxel, Gemcitabine, Irinotecan, Paclitaxel, Pemetrexed, Vinblastine, or Vinorelbine.
- Etopophos® etoposide
- Hycamtin® topotecan
- VePesid® etoposide
- Toposar® etoposide
- Opdivo® nivolumab
- Embodiment 20 The use of Embodiment 16, wherein the cancer is pancreatic ductal cancer and the at least one second therapeutic agent is Gemzar® (Gemcitabine), fluorouracil, Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (irinotecan), bevacizumab, cetuximab, Infugem® (gemcitabine) or Lynparza® (olaparib).
- Gemzar® Gamcitabine
- fluorouracil Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar
- Embodiment 21 The use of Embodiment 16, wherein the cancer is head and neck cancer and the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
- Erbituz® cetuximab
- Taxotere® docetaxel
- Trexall® metalhotrexate
- Keytruda® pembrolizumab
- Opdivo® nivolumab
- Embodiment 22 The use of Embodiment 16, wherein the cancer is prostate cancer and the at least, one second therapeutic agent is Suprefact® (buserelin), Firmagon® (degarelix), Zoladex® (goserelin), Vantas® (histrelin), Eligard® (leuprolide), Orgovyx® (relugolix), Trelstar® (triptorelin), Casodex® (bicalutamide), Eulexin® (flutamide), Nilandron® (nilutamide), Zytiga® (biraterone acetate), Erleada® (apalutamide), or Xtandi® (enzalutamide).
- Embodiment 23 The use of Embodiment 16, wherein the at least one second therapeutic agent is a STING agonist.
- Embodiment 24 The use of any one of Embodiments 1-23, wherein the subject is (a) not infected with the HIV virus, (b) not suspected of being infected with the HIV virus, (c) not being treated for the HIV virus, and/or (d) not being treated to prevent the HIV virus.
- Embodiment 25 The use of any one of Embodiments 1-24, wherein the cells of the cancer are suspected to or exhibit deficiency of a DDR enzyme, e.g., one or more DDR enzymes of Table C, e.g., Pol ⁇ , Pol ⁇ , and/or Pol ⁇ , or the cells of the cancer are suspected to or exhibit amplification of a DDR gene, e.g., one or more DDR genes of Table
- C e.g., POLII, POLM, and/or POLQ.
- Embodiment 1 A method of treating cancer in a patient, wherein the cells of the cancer are suspected to or exhibit deficiency of a DNA repair enzyme, comprising administering to the patient an effective amount of a reverse transcriptase inhibitor (RTI) that is also a Pol ⁇ inhibitor, with the proviso that, the RTI is not ddC.
- RTI reverse transcriptase inhibitor
- Embodiment 2 The method of Embodiment 1, further comprising administering at least one second agent that is useful for the treatment of cancer.
- Embodiment 3 The method of Embodiment 2, wherein the at least one second agent that is useful for the treatment of cancer is a poly ADP ribose polymerase
- PARP PARP inhibitor
- ATM inhibitor an ATM inhibitor
- weel inhibitor an ATM inhibitor
- ATR inhibitor an ATR inhibitor
- Embodiment 4 The method of Embodiment 1, wherein the cells are resistant to PARP inhibition.
- Embodiment 5 The method of Embodiment 2, wherein the second agent is a
- Embodiment 6 The method of Embodiment 5, wherein the P AR P inhibitor is olaparib, rucaparib, niraparib or talazoparib.
- Embodiment 7 The method of any one of Embodiments 1-6, wherein the DNA repair enzyme is encoded by at least one homologous recombination (HR) gene.
- HR homologous recombination
- Embodiment 8 The method of Embodiment 7, wherein the at least one HR gene is ATM, ATR, BRCA1, BRCA2, BARD1, RAD51C, RAD50, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 (FANCN), FANCP (BTBD12), ERCC4 (FANCQ), FPEN, CDK12, MRE11, NBS1, NBN, CLASPIN, BLM, WRN, SMARCA2, SMARCA4 LIG1, RPA1, BRI P l or PTEN.
- the at least one HR gene is ATM, ATR, BRCA1, BRCA2, BARD1, RAD51C, RAD50, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 (FANCN),
- Embodiment 9 The method of any one of Embodiments 1-8, wherein the RTI is lamivudine (3TC), zidovudine (AZT), tenofovir, tenofovir disoproxil, tenofovir alafenamide, stavudine (d4T), didanosine (ddl), emtricitabine (FTC), entecavir (ETV), 2',3'-dideoxyguanosine (ddG), 2’, 3 '-dideoxyadenosine (ddA), 2'-fluoro-2',3'- dideoxyarabinosyladenine (F-ddA), efavirenz (EFV), nevirapine (NVP), or abacavir (ABC), adefovir dipivoxil, telbivudine, or islatravir.
- the RTI is lamivudine (3TC), zidovudine (AZT
- Embodiment 10 The method of any one of Embodiments 1-8, wherein the RTI is any one or more of the compounds of Table A, or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof.
- Embodiment 11 The method of any one of Embodiments 1-8, wherein the RTI is any one or more of the compounds of Table B, or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof.
- Embodiment 12 The method of Embodiments 1-11, wherein the cancer is breast cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and/or BRCA2 genes.
- Embodiment 13 The method of Embodiments 1-11, wherein the cancer is prostate cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and or BRCA2 genes.
- Embodiment 14 The method of Embodiments 1-11, wherein the cancer is ovarian cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and /or BRCA2 genes.
- Embodiment 15 The method of Embodiments 1-11, wherein the cancer is pancreatic cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and/or BRCA2 genes.
- Embodiment 16 The method of any one of Embodiments 1-15, wherein the cells of the cancer exhibit overexpression of PolQ compared to the corresponding cells that are not cancer cells.
- Embodiment 17 The method of any one of Embodiments 1-16, wherein the RTI inhibits human LINE- 1 retrotransposition with a half maximal inhibitory’ concentration of less than 100 nM in a HeLa cell-based dual-luciferase assay.
- Embodiment 18 The method of any one of Embodiments 1-16, wherein the RTI inhibits human LINE-1 retrotransposition with a half maximal inhibitory concentration of less than 50 nM in a HeLa cell-based dual-luciferase assay.
- Embodiment 19 The method of any one of Embodiments 1-16, wherein the RTI inhibits human LINE-1 retrotransposition with a half maximal inhibitory concentration of less than 10 nM in a HeLa cell-based dual-luciferase assay.
- Embodiment 20 The method of Embodiment 2 for the treatment of breast cancer, wherein the at least one second therapeutic agent is Soltamox® (tamoxifen), Arimidex® (anastrozole), Femara® (letrozole), Aromasin® (exemestane), Herceptin® (trastuzumab), Abraxane® (paclitaxel), Cytoxan® (cyclophosphamide), Taxol® (paclitaxel), Afinitor® (everolimus), Taxotere® (docetaxel), Xeloda® (capecitabine), Trexall® (methotrexate), Faslodex (fulvestrant), Adriamycin® (doxorubicin), Perjeta® (pertuzumab), Gemzar (gemcitabine), Tykerb® (lapatinib), Adrucil® (fluorouracil), Ibrance® (palbociclib), Verzenio® (abemacic
- Embodiment 21 The method of Embodiment 2 for the treatment of colon cancer, wherein the at least one second therapeutic agent is Xeloda® (capecitabine), El oxatin® (oxaliplatin), fluorouracil, Avastin® (bevacizumab), leucovorin, Camptosar® (irinotecan), Stivarga® (regorafenib), Erbitux® (cetuximab), Vectibix® (panitumumab), Lonsurf® (tipiracil/trifluridine), Zaltrap® (ziv-aflibercept), Betaseron® (interferon betalb), Fusilev® (levoleucovorin), Wellcocorin® (methotrexate), Keytruda® (pembrolizumab), Mvasi® (bevacizumab-awwb), Cyramza® (ramucirumab), Yervoy®
- Embodiment 22 The method of Embodiment 2 for the treatment of lung cancer, wherein the at least one second therapeutic agent is Etopophos® (etoposide), Hycamtin® (topotecan), VePesid® (etoposide), Toposar® (etoposide), Opdivo® (nivolumab), Keytruda® (pembrolizumab), Tecentriq® (atezolizumab), Itnfinizi® (durvalumab), methotrexate, cyclophosphamide, Carboplatin, Cisplatin, docetaxel, Gemcitabine, Irinotecan, Paclitaxel, Pemetrexed, Vinblastine, or Vinorelbine.
- Etopophos® etoposide
- Hycamtin® topotecan
- VePesid® etoposide
- Toposar® etoposide
- Opdivo® nivolumab
- Embodiment 23 The method of Embodiment 2 for the treatment of pancreatic ductal cancer, wherein the at least one second therapeutic agent is Gemzar® (Gemcitabine), fluorouracil, Afmitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (irinotecan), bevacizumab, cetuximab, Infugem® (gemcitabine) or Lynparza® (olaparib).
- Gemzar® Gamcitabine
- fluorouracil fluorouracil
- Afmitor® everolimus
- Tarceva® erlotinib
- Abraxane® paclitaxel
- capecitabine Sutent® (sunitinib)
- Embodiment 24 The method of Embodiment 2 for the treatment of head and neck cancer, wherein the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
- the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
- Embodiment 25 The method of Embodiment 2 for the treatment of prostate cancer, wherein the at least one second therapeutic agent is Supr efact® (buserelin), Firmagon® (degarelix), Zoladex® (goserelin), Vantas® (histrelin), Eligard® (leuprolide), Orgovyx® (relugolix), Trelstar® (triptorelin), Casodex® (bicalutamide), Eulexin® (flutamide), Nilandron® (nilutamide), Zytiga® (abiraterone acetate), Erleada® (apalutamide), or Xtandi® (enzalutamide).
- Supr efact® buserelin
- Firmagon® degarelix
- Zoladex® goserelin
- Vantas® histrelin
- Eligard® leuprolide
- Orgovyx® relugolix
- Trelstar® tripto
- Embodiment 26 The method of Embodiment 2, wherein the at least one second therapeutic agent is a STING agonist.
- Embodiment 27 The method of any one of Embodiments 1-26, wherein the patient is (a) not infected with the HIV virus, (b) not suspected of being infected with the HIV virus, (c) not being treated for the HIV virus, and/or (d) not being treated to prevent the HIV virus.
- Embodiment 28 The method of any one of Embodiments 1-27 wherein the
- RTI is a nucleoside reverse transcriptase inhibitor (NRTI).
- Embodiment 29 A kit for carrying out the method of any one Embodiments
- kits comprising (i) a RTI; and (ii) and instructions for administering the RTI to a patient having cancer.
- Embodiment 30 The kit of Embodiment 29, wherein the kit contains instructions for admini stering the RTI according to an intermittent dosing schedule.
- Embodiment 31 The kit of Embodiment 29 or 30 further comprising at least one second therapeutic agent for the treatment of cancer.
- Embodiment 32 The kit of Embodiment 29 or 30, further comprising instructions for administering the NRTI together with at least one second therapeutic agent for the treatment of cancer.
- Step 1 O-((2R,3R,4S,5R)-2-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-4-
- Step 2 N-(l-((2R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-5- methyltetrahydroforan-2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)benzamide.
- Step 3 4-amino-1-((2R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-5- methyltetrahydrofuran-2-yl)pyrimidin-2(1H)-one.
- Step 4 4-amino-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)-5- methyltetrahydrofuran-2-yl)pyrimidin-2(1H)-one (Cpd. No. 5).
- a flame-dried round-bottomed flask equipped with a magnetic stirrer bar was charged with a solution of 4-amino-1- ((2R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-5-methyltetrahydrofuran-2-yl)pyrimidin- 2(1H)-one (186 mg, 441 pmol) in MeOH (17.7 mL) under nitrogen atmosphere.
Abstract
Disclosed is a method for treating cancer by administering a damage repair (DDR) enzyme inhibitor to a patient in need thereof whose cancer cells are suspected of or have a deficiency of a DNA repair enzyme.
Description
METHOD FOR TREATING CANCER WITH A DNA DAMAGE REPAIR ENZYME INHIBITOR
BACKGROUND
Field
[0001] The present disclosure is in the field of medicinal chemistry. In particular, the disclosure provides a method for treating cancer by administering a reverse transcriptase inhibitor (RTI), that is also a DNA polymerase theta (PolQ) inhibitor to a patient in need thereof whose cancer cells have a deficiency or is suspected of having a deficiency of a DNA repair enzyme. Exemplary RTIs include lamivudine (3TC), stavudine (d4T), emtricitabine (FTC), abacavir (ABC), tenofovir alafenamide, zidovudine (AZT), didanosine (ddl), tenofovir disoproxil, adefovir dipivoxil, entecavir (ETV), and telbivudine. In some embodiments, the RTI is a nucleoside reverse transciptase inhibitor (NRTI). The disclosure also provides a method for treating cancer by administering a damage repair (DDR) enzyme inhibitor, e.g. a Pol θ, Pol μ, and/or Pol μ inhibitor. In some embodiments, the cancer is breast, colon, lung, pancreatic ductal, prostate, ovarian, or head and neck cancer.
Background
[0002] Robust repair of DNA double-strand breaks (DSBs) is essential for the maintenance of genome stability and cell viability. DSBs can be repaired by one of three main pathways: homologous recombination (HR), non-homologous end-joining (NHEJ) and alternative NHEJ (alt-NHEJ). Microhomology-mediated end-joining (MMEJ) is the most well characterized alt-NHEJ mechanism. HR-mediated repair is a high-fidelity mechanism essential for accurate error-free repair, preventing cancer-predisposing genomic stability. Conversely, NHEJ and MMEJ are error-prone pathways that can leave mutational scars at the site of repair. MMEJ can function parallel to both HR and NHEJ pathways (Truong et al. PNAS 2013, 110 (19), 7720-7725). See also WO2021/123785.
[0003 ] The survival of cancer cells, unlike normal cells, is often dependent on the mis-regulation of DNA damage response pathways. For example, an increased dependency on one pathway (often mutagenic) to cope with either the inactivation of another one, or the enhanced replication stress resulting from increased proliferation. An aberrant DDR
can also sensitise cancer cells to specific types of DNA damage, thus, defective DDR can be exploited to develop targeted cancer therapies. Crucially, cancer cells with impairment or inactivation of HR and NHEJ become hyper-dependent, on MMEJ-mediated DNA repair. Genetic, cell biological and biochemical data have identified PolQ (UniProtKB - 075417 (DPOLQ HUMAN) as the key protein in MMEJ (Kent et al., Nature Structural & Molecular Biology’ (2015), 22(3), 230-237, Mateos-Gomez et al., Nature (2015), 518(7538), 254-257). PolQ is multifunctional enzyme, which comprises an N-terminal helicase domain (SF2 HEL308-type) and a C-terminal low-fidelity DNA polymerase domain (A-type) (Wood & Doublie, DNA Repair (2016), 44, 22-32). Both domains have been shown to have concerted mechanistic functions in MMEJ. The helicase domain mediates the removal of RPA protein from ssDNA ends and stimulates annealing. The polymerase domain extends the ssDNA ends and fills the remaining gaps.
[0004] Therapeutic inactivation of PolQ would thus disable the ability of cells to perform MMEJ and provide a targeted strategy in an array of defined tumor contexts. PolQ has been shown to be essential for the survival of HR-defective (HRD) cells (e.g. synthetic lethal with FA/BRCA-deficiency) and is up-regulated in HRD tumor cell lines (Ceccaldi et al.. Nature (2015), 518(7538), 258-262). In vivo studies also show that PolQ is significantly over expressed in subsets of HRD ovarian, uterine and breast cancers with associated poor prognosis (Higgins et al., Oncotarget (2010), 1, 175-184, Lemee et al., PNAS (2010), 107(30), 13390-13395, Ceccaldi et al. (2015), supra). Importantly, PolQ is largely repressed in normal tissues but has been shown to be upregulated in matched cancer samples thus correlating elevated expression with disease (Kawamura et al., International Journal of Cancer (2004), 109(1), 9-16). Secondly, its suppression or inhibition confers radio-sensitivity in tumor cells. Finally, PolQ inhibition prevents the MMEJ -dependent functional reversion of BRCA2 mutations that underlies the emergence of cisplatin and PARPi resistance in tumors. There is a need to provide effective DDR inhibitors, e.g., a Pol θ, Pol η, and/or Pol μ inhibitor, for the treatment of cancer.
BRIEF SUMMARY
[0005] In some embodiments, provided is a method of treating cancer in a patient, wherein the cells of the cancer are suspected of or exhibit deficiency of a DNA repair enzyme, comprising administering to the patient an effective amount of a reverse transcriptase
inhibitor (RTI) that is also a Pol θ inhibitor, with the proviso that the RTI is not ddC (also known as zalcitabine or 2'-3 '-dideoxy cytidine).
[0006] In some embodiments, provided is a method of treating cancer in a patient, comprising administering to the patient an effective amount of DDR enzyme, e.g., Pol0, inhibitor.
[0007] In some embodiments, provided is a method of treating cancer in a patient, wherein the cells of the cancer are suspected of or exhibit defi ciency of a DDR enzyme, comprising administering to the patient an effective amount of DDR enzyme, e.g., Pol0, inhibitor.
[0008] In some embodiments, provided is a method of treating cancer in a patient, comprising administering to the patient an effective amount of DDR enzyme, e.g., Pol0, inhibitor.
[0009] In some embodiments, provided is a method of treating cancer in a patient, wherein the cells of the cancer are suspected of or exhibit deficiency of a DNA repair enzyme, comprising administering to the patient an effective amount of DDR enzyme, e.g., PolG, inhibitor.
[0010] In some embodiments, the method further comprises administering a second agent that is a poly ADP ribose polymerase (PARI5) inhibitor, an ATM inhibitor, a weel inhibitor, a CHK inhibitor, or an ATR inhibitor.
[0011] In some embodiments, the cells are resistant to PARP inhibition. In some embodiments, the second agent is a PARP inhibitor. In some embodiments, the PARP inhibitor is olaparib, rucaparib, niraparib or talazoparib.
[0012] In some embodiments, the DDR enzyme is encoded by at least one homologous recombination (HR) gene. In some embodiments, the at least one HR gene is ATM, ,ATR, BRCA1, BRCA2, BARD1, RAD51C, RAD50, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 (FANCN), FANCP (BTBD12), ERCC4 (FANCQ), FPEN, CDK12, MRE11, NBS 1, NBN, CLASPIN, BLM, WRN, SMARCA2, SMARCA4 LIG1 , RPA1, BRIP1 or PTEN.
[0013] In some embodiments, the RTI is lamivudine (3TC), zidovudine (AZT), tenofovir, tenofovir disoproxil, tenofovir alafenamide, stavudine (d4T), didanosine (ddl), emtricitabine (FTC), entecavir (ETV), 2',3'-dideoxyguanosine (ddG), 2’,3’- dideoxyadenosine (ddA), 2'-fluoro-2',3'-dideoxyarabinosyladenine (F-ddA), efavirenz (EFV), nevirapine (NVP), abacavir (ABC), adefovir dipivoxil, or telbivudine.
[0014] In some embodiments, the RTI and/or DNA damage repair enzyme inhibitor is a compound of Formula I:
or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof, wherein:
[0016] R1 is selected from the group consisting of hydrogen and -OH;
[0017] R2 is selected from the group consisting of methyl, ethynyl, and -CN;
[0018] R3 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo and methyl;
[0019] R4 is selected from the group consisting of -NH2 and -OH;
[0020] R3 is selected from the group consisting of -NH2 and -OH; and
[0021] R6 is selected from the group consisting of hydrogen, fluoro, chloro, and -NH2
[0022] In some embodiments, the RTI and/or DNA damage repair enzyme inhibitor is a compound of Formula II:
or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof, wherein R1, R“, R3, and R4 are as defined in connection with Formula I.
[0023] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound of Formula II, wherein R3 is hydrogen.
[0024] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound of Formula II, wherein R3 is selected from the group consisting of fluoro and chloro.
[0025] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound of Formula II, wherein R3 is methyl.
[0026] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound of Formula II, wherein R4 is -NH2.
[0027] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound of Formula II, wherein R4 is -OH.
[0028] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound of Formula III:
or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof, wherein R1, R2, R5, and R° are as defined in connection with Formula I.
[0029] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound of Formula III, wherein R5 is -NH2.
[0030] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound of Formula III, wherein R5 is -OH.
[0031] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound of Formula III, wherein R6 is hydrogen.
[0032] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound of Formula III, wherein R6 is chloro.
[0033] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound of Formula III, wherein R6 is fluoro.
[0034] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound of Formula III, wherein R6 is -NH2.
[0035] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound of any one of Formulae I-III, wherein R1 is hydrogen.
[0036] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound of any one of Formulae I-III, wherein R1 is -OH.
[0037] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound of any one of Formulae I-III, wherein R2 is methyl.
[0038] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound of any one of Formulae I-III, wherein R2 is ethynyl.
[0039] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound of any one of Formulae I-III, wherein R2 is -CN.
[0040] In some embodiments, the RTI and/or DDR enzyme inhibitor is any one or more of the compounds of Table A, or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof
Table A
[0041] In some embodiments, the RTI and/or DDR enzyme inhibitor is any one or more of the compounds of Table B, or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof.
[0042] In some embodiments, the RTI and/or DDR enzyme inhibitor is a compound Table A, Table B, or Table 3. See below. In some embodiments, the compound of Table A, Table B, or Table 3 is a RTI and a DDR enzyme inhibitor. In some embodiments, the compound of Table A, Table B, or Table 3 is a RTI inhibitor. In some embodiments, the compound of Table A, Table B, or Table 3 is a DDR enzyme inhibitor, e.g., one or more of the DDR enzymes of Table C. In some embodiments, the compound of Table A, Table B, or Table 3 is a Pol θ inhibitor. In some embodiments, the compound of Table A, Table B, or Table 3 is a Pol μ inhibitor. In some embodiments, the compound of Table A, Table B, or Table 3 is a Pol μ inhibitor.
[0043] In some embodiments, the DDR enzyme inhibitor is a compound of Table 3.
[0044] The compounds above in Tables A and B, and below in Table 3 may be found and prepared as described, for example, in Nomura et al., J. Med. Chem. 42:2901-2908 (1999); Ohrui et al., J. Med. Chem. 43:4516-4525 (2000); Ohrui, H., Proc. Jpn. Acad. Ser. B 87:53-65 (2011); Banuelos-Sanchez et al., Cell Chemical Biology 26: 1095-1109 (2019); Kirby et al ., Antimicrobial Agents and Chemotherapy 57:6254-6264 (2013); Kodama et al.. Antimicrobial Agents and Chemotherapy 45: 1539-1546 (2013); Higashi-Kuwata et al., Journal of Hepatology 74: 1075-1086 (2021); JP Patent No. 6767011; US Patent No. 10,933,067, and/or as decscribed in EXAMPLE 2 below.
[0045] In some embodiments, the cancer i s breast cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCAI and/or BRCA2 genes.
[0046] In some embodiments, the cancer is prostate cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and or BRCA2 genes.
[0047] In some embodiments, the cancer is ovarian cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCAI and /or BRCA2 genes.
[0048] In some embodiments, the cancer is pancreatic cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCAI and/or BRCA2 genes.
[0049] In some embodiments, the cells of the cancer exhibit overexpression of PolQ compared to the corresponding cells that are not cancer cells.
[0050] In some embodiments, the RTI inhibits human LINE-1 retrotransposition with a half maximal inhibitor}' concentration of less than 100 nM in a HeLa cell-based dualluciferase assay. In some embodiments, the RTI inhibits human LINE-1 retrotransposition with a half maximal inhibitory concentration of less than 50 nM in a HeLa cell-based dualluciferase assay. In some embodiments, the RTI inhibits human LINE-1 retrotransposition with a half maximal inhibitory concentration of less than 10 nM in a HeLa cell-based dualluciferase assay.
[0051] In some embodiments, the method further comprises administering a therapeutically effective amount of at least one second therapeutic agent useful for treating the cancer.
[0052] In some embodiments, the method is for the treatment of breast cancer, wherein the at least one second therapeutic agent is Soltamox® (tamoxifen), Arimidex® (anastrozole), Femara® (letrozole), Aromasin® (exemestane), Herceptin® (trastuzumab), Abraxane® (paclitaxel), Cytoxan® (cyclophosphamide), Taxol® (paclitaxel), Afinitor® (everolimus), Taxotere® (docetaxel), Xeloda® (capecitabine), Trexall® (methotrexate), Faslodex (fulvestrant), Adriamycin® (doxorubicin), Perjeta® (pertuzumab), Gemzar (gemcitabine), Tykerb® (lapatinib), Adrucil® (fluorouracil), Ibrance® (palbociclib), Verzenio® (abemaciclib), Fareston® (toremifene), Halaven® (eribulin), Menest, Kadcyla® (ado- trastuzumab emtransine), Androxy® (fluoxymesterone), Avastin® (bevacizumab), esterified estrogens, Herzuma® (trastuzumab), Ixempra® (ixabepilone), Kanjinti® (trastuzumab), Kisqali® (ribociclib), Ogivri® (trastuzumab), Ontruzant® (trastuzumab), Tepadina® (thiotepa), Trazimera® (trastuzumab), Velban® (vinblastine), Piqray®
(alpelisib), Tecentriq® (atezolizumab), Enhertu® (fam-trastuzumab deruxtecan), Herceptin, Hylecta™ (hyaluronidase/trastuzumab), Infugem® (gemcitabine), Kisqali® Femara® Co-Pack (ribociclib and letrozole), Talzenna® (talazoparib), Trodelvy® (sacituzumab) or Tukysa™ (tukatinib).
[0053] In some embodiments, the method is for the treatment of colon cancer, wherein the at least one second therapeutic agent is Xeloda® (capecitabine), Eloxatin® (oxaliplatin), fluorouracil, Avastin® (bevacizumab), leucovorin, Camptosar® (irinotecan), Stivarga® (regorafenib), Erbitux® (cetuximab), Vectibix® (panitumumab), Lonsurf® (tipiracil/trifluridine), Zaltrap® (ziv-aflibercept), Betaseron® (interferon beta-lb), Fusilev® (levoleucovorin), Wellcocorin® (methotrexate), Keytruda® (pembrolizumab), Mvasi® (bevacizumab-awwb), Cyramza® (ramucirumab), Yervoy® (ipilmumab), Opdivo® (nivolumab), Braftovi® (encorafenib), Khapzory® (levoleucovorin) or Zirabev® (bevacizumab-bvzr).
[0054] In some embodiments, the method is for the treatment of lung cancer, wherein the at least one second therapeutic agent is Etopophos® (etoposide), Hycamtin® (topotecan), VePesid® (etoposide), Toposar® (etoposide), Opdivo® (nivolumab), Keytruda® (pembrolizumab), Tecentriq® (atezolizumab), Imfinizi® (durvalumab), methotrexate, cyclophosphamide, Carboplatin, Cisplatin, docetaxel, Gemcitabine, Irinotecan, Paclitaxel, Pemetrexed, Vinblastine, or Vinorelbine.
[0055] In some embodiments, the method is for the treatment of pancreatic ductal cancer, wherein the at least one second therapeutic agent is Gemzar® (Gemcitabine), fluorouracil, Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (irinotecan), bevacizumab, cetuximab, Infugem® (gemcitabine) or Lynparza® (olaparib).
[0056] In some embodiments, the method is for the treatment of head and neck cancer, wherein the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
[0057] In some embodiments, the method is for the treatment of prostate cancer, wherein the at least one second therapeutic agent is Suprefact® (buserelin), Firmagon® (degarelix), Zoladex® (goserelin), Vantas® (histrelin), Eligard® (leuprolide), Orgovyx® (relugolix),
Trelstar® (triptorelin), Casodex® (bicalutamide), Eulexin® (flutamide), Nilandron® (nilutamide), Zytiga® (biraterone acetate), Erleada® (apalutamide), or Xtandi® (enzalutamide).
[0058] In some embodiments, the at least one second therapeutic agent is a STING agonist.
[0059] In some embodiments, the patient is (a) not infected with the HIV virus, (b) not suspected of being infected with the HIV virus, (c) not being treated for the HIV virus, and/or (d) not being treated to prevent the HIV virus.
[0060] Also provided is a kit for carrying out the methods described herein, the kit comprising (i) a RTI and/or DDR enzyme inhibitor; and (ii) and instructions for administering the RTI and/or DDR enzyme inhibitor to a patient having cancer. In some embodiments, the kit contains instructions for administering the RTI and/or DDR enzyme inhibitor according to an intermittent dosing schedule. In some embodiments, the kit further comprises at least one second therapeutic agent for the treatment of cancer. In some embodiments, the kit further comprises instructions for administering the RTI and/or DDR enzyme inhibitor together with at least one second therapeutic agent for the treatment of cancer.
DETAILED DESCRIPTION
[0061] In one embodiment, provided is a method for treating cancer in patient in need thereof comprising administering a therapeutically effective amount of a reverse transcriptase inhibitor (RTI) that also inhibits PolQ, wherein the cells of the cancer are suspected of or exhibit deficiency of a DDR enzyme. Without wishing to be bound by any particular theory, the combination of, e.g., PolQ inhibition, and a deficiency of a DDR enzyme causes synthetic lethality to the cancer cells. In some embodiments, the deficiency is a reduction in the activity of a DDR enzyme. In some embodiments, the definiciency is an absence of activity of a DDR enzyme. The deficiency of the DDR enzyme may be caused any means that results in the deficiency of the DDR enzyme including, but not limited to, genetic variations of the gene encoding the DDR enzyme including mutations (e.g. point mutations), substitutions, deletions, single nucleotide polymorphisms (SNPs), haplotypes, chromosome abnormalities. Copy Number Variation (CNV), epigenetics, DNA inversions, reduction in expression and mis-localisation.
[0062] In another embodiment, provided is a method of treating or preventing cancer in a patient in need thereof, the method comprising administering a therapeutically effective amount of a DDR enzyme inhibitor to the patient. In another embodiment, the DDR enzyme inhibitor is one or more of the DDR enzymes of Table C. In another embodiment, the DDR enzyme inhibitor is a Pol η, Pol μ, or Pol θ inhibitor. In one embodiment, the DDR enzyme inhibitor is a Pol θ (PolQ) inhibitor. In some embodiments, the cancer is a homologous recombinant (HR) deficient cancer. In one embodiment, said homologous recombination genes include any of: ATM, APR, BRCA1, BRCA2, BARD1, RAD51C, RAD50, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 (FANCN), FANCP (BTBDI2), ERCC4 (BANCO), PTEN, CDK12, MRE11, NBS1, NBN, CLASPIN, BLM, WRN SMARCA2, SMARCA4, LIGI , RPA 1, RPA2, BRI Pi and PTEN.
[0063] In another embodiment, the disclosure provides a method for treating cancer in subject in need thereof comprising administering a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Table A, Table B, or Table 3, e.g., a compound of Table 3, wherein the cells of the cancer are suspected of or exhibit amplification of a DDR enzyme or gene. Without wishing to be bound by any particular theory, DDR gene amplification, e.g., overexpression, can lead to chemotherapy resistance and poor overall survival by augmenting DDR. See, e.g., Wu et al., Theranostics 10:3939- 3951 (2020).
[0064] References herein to "non-homologous end-joining deficiency (NHEJD)” refer to any genetic variation which results in a deficiency or loss of function of the resultant homologous recombination gene. Examples of said genetic variation include mutations (e.g. point mutations), substitutions, deletions, single nucleotide polymorphisms (SNPs), haplotypes, chromosome abnormalities, Copy Number Variation (CNV), epigenetics, DNA inversions, reduction in expression and mis-localisation.
[0065] In one embodiment, said non-homologous end-joining genes are selected from any one or more of: LIG4, NHEJ1 , POLL, POLM, PRKDC, XRCC4, XRCC5, XRCC6, and DCLRE1C.
[0066] In some embodiments, the RTI is islatravir, elvucitabine, lamivudine (3TC), zidovudine (AZT), tenofovir, tenofovir disoproxil, tenofovir alafenamide, stavudine (d4T),
didanosine (ddl), emtricitabine (FTC), entecavir (ETV) or abacavir (ABC), wherein the RTI is administered according to an intermittent dosing schedule.
[0067] In one embodiment, the RTI is abacavir (ZIAGEN™), abacavir/lamivudine (Epzicom), abacavir/lamivudine/zidovudine (TRIZIVIRTM), adefovir, alovudine, amdoxovir, apricitabine, ATRIPLA®, BARACLUDE®, BIKT ARV Y®, COVIRACII. ™, DAPD/DXG, D-D4FC, dexelvucitabine, didanosine (VIDEXTM), didanosine extended- release (Videx EC), dOTC, emtricitabine (EMTRIVA™), emtricitabine/tenofovir alafenamide (DESCOVY®), emtricitabine/tenofovir disoproxil fumarate (TRUVADA®), fosalvudine, laniivudine/zidovudine (COMBIVIR™), EVIPLERA™, GENVOYA®, HIVID™, KIVEXA™, lamivudine (EPIVIR™), LODENOSINE™, ODEFSEY®, PREVEON®, racivir, stampidine, stavudine (ZERIT™), STRIBILD® TENOFOVIR™, tenofovir disoproxil fumarate (VIREAD™), TRIUMEQ®, Trizivir, VEMLIDY®, and zi dovudine (RETROVIR™) .
[0068] In another embodiment, the RTI is a LINE-1 inhibitor.
[0069] In another embodiment, the RTI is islatravir, elvucitabine, lamivudine (3TC), zidovudine (AZT), tenofovir, tenofovir disoproxil, tenofovir alafenamide, stavudine (d4T), didanosine (ddl), emtricitabine (FTC), entecavir (ETV), 2',3’-dideoxyguanosine (ddG), 2', 3 '-dideoxyadenosine (ddA), 2'-fluoro-2',3 '-dideoxyarabinosyladenine (F-ddA), efavirenz (EFV), nevirapine (NVP), or abacavir (ABC).
[0070] In another embodiment, the RTI is lamivudine (3TC), stavudine (d4T), emtricitabine (FTC), abacavir (ABC), tenofovir alafenamide, zidovudine (AZT), didanosine (ddl), tenofovir disoproxil, adefovir dipivoxil, entecavir (ETV), or telbivudine. [0071] In another embodiment, the RTI is islatravir.
[0072] In another embodiment, the RTI is lamivudine (3TC).
[0073] In another embodiment, the RTI is stavudine (d4T).
[0074] In another embodiment, the RTI is emtricitabine (FTC).
[0075] In another embodiment, the RTI is abacavir (ABC).
[0076] In another embodiment, the RTI is tenofovir alafenamide.
[0077] In another embodiment, the RTI is zidovudine (AZT).
[0078] In another embodiment, the RTI is didanosine (ddl).
[0079] In another embodiment, the RTI is tenofovir disoproxil.
[0080] In another embodiment, the RTI is adefovir dipivoxil.
[0081] In another embodiment, the RTI is entecavir.
[0082] In another embodiment, the RTI is telbivudine.
[0083] In some embodiments, provided is a method for treating cancer, e.g., breast, colon, king, pancreatic ductal, prostate, ovarian, or head and neck cancer, by administering elvucitabine a patient in need thereof.
Elvucitabine and its method of synthesis is described in U.S. Pat. No. 5,627,160.
[0085] The term reverse transcriptase inhibitor (RTI) as used herein refers to a nucleoside or nucleotide reverse transcriptase inhibitor. RTIs inhibit human reverse transcriptase activity, e.g., with an IC50 of about 50 μM or less, a suitable assay, e.g., a colorimetric enzyme immunoassay. In another embodiment, the IC50 is 1 μM or less. In another embodiment, the IC50 is 0,5 μM or less. In another embodiment, the IC50 is 0.25 μM or less. In another embodiment, the IC50 is 0.15 μM or less. In another embodiment, the IC50 is 0.1 μM or less. In another embodiment, the IC50 is 0.05 μM or less. In another embodiment, the IC50 is 0.01 μM or less. In another embodiment, the IC50 is 0.005 μM or less. In some embodiments, the RTI a nucleoside reverse transcriptase inhibitor (NRTI). In some embodiments, the RTI a nucleotide reverse transcriptase inhibitor. In some embodiments, the RTI is also a LINE-1 inhibitor.
[0086] The term "DNA repair enzyme inhibitor" or "DDR enzyme inhibitor" and the like as used herein refers to a compound that inhibits the activity of one or more human DNA damage repair enzymes with a half-maximal inhibitory concentration (IC50) of 100 μM or less. In one embodiment, a DDR enzyme inhibitor inhibits human DDR enzyme activity an IC50 of 10 μM or less. In another embodiment, a DDR enzyme inhibitor inhibits human DDR enzyme activity with an IC50 of 1 μM or less. In another embodiment, a DDR enzyme inhibitor inhibits human DDR enzyme activity with an IC50 of 500 nM or less. In another embodiment, a DDR enzyme inhibitor inhibits human DDR enzyme activity with an IC50 of 100 nM or less. In another embodiment, a DDR enzyme inhibitor inhibits human DDR enzyme activity with an IC50 of 50 nM or less. In another embodiment, a DDR
enzyme inhibitor inhibits human DDR enzyme activity with an IC50 of 10 nM or less. Representative DDR enzymes are encoded by genes provided in Table Al . Representative DDR inhibitors are provided, for example, in Table 3.
[0087] The compounds disclosed herein may be phosphorylated in a cell by the addition of one, two, or three phosphate groups to form the corresponding mono, di-, or triphosphates as shown in Scheme 1 for Cpd. No. 2:
Without wishing to be bound by any particular theory, these phosphorylated compounds inhibit DDR enzymes following admistration to a subject. As such, these compounds can be used, for example, to treat or prevent cancers wherein DDR enzymes play a causative role.
[0088] Again, without wishing to be bound by any particular theory, cancer cells often acquire mutations in DDR genes, making them dependent on remaining DNA repair pathways. Dependence on TMEJ, for example, is characterized by an increased Pol θ expression and is associated with poor patient prognosis. Inhibition of Pol θ in Pol θ-dependent cancers leads to synthetic lethality. This is well described for malignancies deficient in homologous recombination, e.g., due to mutations in BRCA1 or BRCA2. See, e.g., Schrempt et al., Trends in Cancer 7:98-111 (2021) https://d0i.0rg/l 0.1016/j .trecan.2020.09.007.
[0089] In one embodiment, a Compound of the Disclosure is synthetic lethal in cancers with HR or NHEJ deficiency,
[0090] The term "PolQ inhibitor" or " Pol θ inhibitor" as used herein refers to a compound that inhibits human PolQ activity with a half-maximal inhibitory/ concentration (IC50) of 100 nM or less. In some embodiments, the PolQ inhibitor inhibits PolQ activity with an IC50 of less than 50 nM. In other embodiments, the PolQ inhibitor inhibits PolQ activity
with an IC50 of less than 10 nM. A PolQ inhibitor assay is disclosed in WO2021/123785, the disclosure of which is fully incorporated by reference. In some embodiments, the phosphorylated species of the compounds disclosed herein, see Scheme 1, are POLQ inhibitors. In some embodiments, the triphosphates of the compounds disclosed herein are POLQ inhibitors. Representative triphosphates (TP) of the compounds disclosed herein are provided in Table 1 A.
[0091] The term "LINE-1 inhibitor" as used herein refers to a compound that inhibits human LINE-1 retrotransposition, e.g., with an IC50 of about 50 μM or less in a HeLa cellbased dual -luciferase assay. See also Jones et al., (2008) PLoS ONE 3(2): el 547. doi:10.1371/joumal. pone.0001547; Xie et al., (2011) Nucleic Acids Res. 39(3): e!6. doi: 10.1093/nar/gkql076. In another embodiment, the IC50 is 1 μM or less. In another embodiment, the IC50 is 0.5 μM or less. In another embodiment, the IC50 is 0.25 μM or less. In another embodiment, the IC50 is 0.15 μM or less. In another embodiment, the IC50 is 0.1 μM or less. In another embodiment, the IC50 is 0.05 μM or less. In another embodiment., the IC50 is 0.01 μM or less. In another embodiment, the IC50 is 0.005 μM or less. In some embodiments, the LINE-1 inhibitor is also a nucleoside reverse transcriptase inhibitor (NRTI). In some embodiments, the LINE-1 inhibitor is also a PolQ inhibitor. LINE-1 inhibitors are described, for example, in WO 2020/154656 and Banuelos-Sanchez et al., Cell Chemical Biology 26:1095-1109 (2019). Non-limiting exemplary LINE-1 inhibitors include islatravir, elvucitabine, lamivudine (3TC), zidovudine (AZT), tenofovir, tenofovir disoproxil, tenofovir alaphenamide, stavudine (d4T), didanosine (ddl), emtricitabine (FTC), entecavir (ETV), 2',3'-dideoxyguanosine (ddG),
2', 3 '-dideoxyadenosine (ddA), 2'-fluoro-2',3 '-dideoxyarabinosy ladenine (F-ddA), efavirenz (EFV), nevirapine (NVP), and abacavir (ABC).
[0092] The term "biological sample" as used herein refers any tissue or fluid from a subject that is suitable for detecting a biomarker. Examples of useful biological samples include, but are not limited to, biopsi ed tissues and/or cells, e.g., lymph gland, inflamed tissue, tissue and/or cells involved in a condition or disease, blood, plasma, serous fluid, cerebrospinal fluid, saliva, urine, lymph, cerebral spinal fluid, and the like. Other suitable biological samples will be familiar to those of ordinary skill in the relevant arts. A biological sample can be analyzed for the expression level of a biological compound, e.g., POLQ, using any technique known in the art. Such techniques include, but are not limited to, polymerase chain reaction (PCR) methodology, reverse transcription-polymerase chain reaction (RT-PCR) methodology, or cytoplasmic light chain immunofluorescence combined with fluorescence in situ hybridization (clg-FISH). A biological sample can be obtained using techniques that are well within the scope of ordinary' knowledge of a clinical practitioner. In one embodiment of the disclosure, the biological sample comprises a tissue or blood sample.
[0093] The terms "intermittent dose administration," "intermittent dosing schedule," and similar terms as used herein refer to non-continuous administration of a RTI and/or DDR enzyme inhibitor to a subject. Intermittent dose administration regimens useful in the present disclosure encompass any discontinuous administration regimen that provides a therapeutically effective amount of a RTI and/or DDR enzyme inhibitor to a subject in need thereof. Intermittent dosing regimens can use equivalent, lower, or higher doses of a RTI and/or DDR enzyme inhibitor than would be used in continuous dosing regimens. Advantages of intermittent dose administration include, but are not limited to, improved safety, decreased toxicity, e.g., decreased weight loss, increased exposure, increased efficacy, and/or increased subject compliance. These advantages may be realized when a RTI and/or DDR enzyme inhibitor is administered as a single agent or when administered in combination with one or more additional therapeutic agents, e.g., a STING agonist.
[0094] Examples of treatable cancers include, but are not limited to, any one or more of the cancers of Table I .
[0095] In another embodiment, the cancer is a solid tumor. In another embodiment, the cancer a hematological cancer. Exemplary hematological cancers include, but are not limited to, the cancers listed in Table 2. In another embodiment, the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia.
[0096] In another embodiment, the cancer is a leukemia, for example a leukemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia and mixed lineage leukemia (MLL). In another embodiment the cancer is NUT-midline carcinoma. In another embodiment the cancer is multiple myeloma. In another embodiment the cancer is a lung cancer such as small cell lung cancer (SCLC). In another embodiment the cancer is a neuroblastoma. In another embodiment the cancer is Burkitt’s lymphoma. In another embodiment the cancer is cervical cancer. In another embodiment the cancer is esophageal cancer. In another embodiment the cancer is ovarian cancer. In another embodiment the cancer is colorectal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is breast cancer.
[0097] In another embodiment, the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, breast cancer, bladder cancer, ovary' cancer, glioma, sarcoma, esophageal squamous cell carcinoma, and papillary thyroid carcinoma.
[0098] In another embodiment, islatravir is administered to a subj ect in need thereof to treat breast, colon, lung, pancreatic ductal, prostate, ovarian, or head and neck cancer. In another embodiment, the cancer is breast cancer. In another embodiment, the cancer is colon cancer. In another embodiment, the cancer is lung cancer, e.g., small cell lung cancer or non-small cell lung cancer. In another embodiment, the cancer is pancreatic ductal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is ovarian cancer. In another embodiment, the cancer is head and neck cancer.
[0099] In another embodiment, the cells of the cancer overexpress one or more DDR enzymes.
[0100] In another embodiment, the cells of the cancer overexpress one or more enzymes encoded by the genes of Table Bl.
[0101] In another embodiment, the cells of the cancer overexpress one or more DDR enzymes of Table C.
[0102] In another embodiment, the cancer overexpresses Pol θ.
[0103] In another embodiment, the cancer overexpresses Pol μ.
[0104] In another embodiment, the cancer overexpresses Pol g.
[0105] In another embodiment, the cancer overexpresses TdT.
[0106] In another embodiment, the cancer overexpresses POLQ.
[0107] In another embodiment, the cancer is breast cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and/or BRCA2 genes.
[0108] In another embodiment, the cancer is prostate cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and or BRCA2 genes.
[0109] In another embodiment, the cancer is ovarian cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and /or BRCA2 genes.
[0110] In another embodiment, the cancer is pancreatic cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and/or BRCA2 genes.
[0111] In some embodiments, the patient is also administered at least one second therapeutic agent useful for the treatment of cancer. In some embodiments, the second therapeutic agent useful for the treatment of cancer is is a poly ADP ribose polymerase (PARP) inhibitor, an ATM inhibitor, a weel inhibitor, a CHK inhibitor, or an ATR inhibitor.
[0112] In some embodiments, the PARP inhibitor is olaparib, rucaparib, niraparib or talazoparib.
[0113] In some embodiments, the ATM inhibitor is AZD0156 or M3541 .
[0114] In some embodiments, the ATR inhibitor is AZD6738, M4344, or M6620.
[0115] In some embodiments, the weel inhibitor is AZDI 775.
[0116] In some embodiments, the second therapeutic agent is an epigenetic drug. As used herein, the term "epigenetic drug" refers to a therapeutic agent that targets an epigenetic regulator. Examples of epigenetic regulators include the histone lysine methyltransferases, histone arginine methyl transferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases. Histone deacetylase inhibitors include, but are not limited to, vorinostat.
[0117] In another embodiment, chemotherapeutic agents or other anti -proliferative agents can be combined with islatravir to treat proliferative diseases and cancer. Examples of therapies and anticancer agents that can be used in combination with islatravir include surgery, radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes), endocrine therapy, a biologic response modifier (e.g., an interferon, an interleukin, tumor necrosis factor (TNF), hyperthermia and cryotherapy, an agent to attenuate any adverse effect (e.g., an antiemetic), and any other approved chemotherapeutic drug.
[0118] Examples of antiproliferative compounds include, but are not limited to, an aromatase inhibitor; an anti -estrogen, an anti -androgen; a gonadorelin agonist; a topoisomerase I inhibitor; a topoisomerase II inhibitor; a microtubule active agent; an alkylating agent; a retinoid, a carontenoid, or a tocopherol; a cyclooxygenase inhibitor; an
MMP inhibitor; an mTOR inhibitor; an antimetabolite; a platin compound; a methionine aminopeptidase inhibitor; a bisphosphonate; an antiproliferative antibody; a heparanase inhibitor; an inhibitor of Ras oncogenic isoforms; a telomerase inhibitor; a proteasome inhibitor; a compound used in the treatment of hematologic malignancies; a Flt-3 inhibitor; an Hsp90 inhibitor; a kinesin spindle protein inhibitor; a MEK inhibitor; an antitumor antibiotic; a nitrosourea; a compound targeting/decreasing protein or lipid kinase activity, a compound targeting/decreasing protein or lipid phosphatase activity, or any further anti- angiogenic compound.
[0119] Nonlimiting exemplary' aromatase inhibitors include, but are not limited to, steroids, such as atamestane, exemestane, and formestane, and non-steroids, such as aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole, and letrozole.
[0120] Nonlimiting anti -estrogens include, but are not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Anti-androgens include, but are not limited to, bicalutamide. Gonadorelin agonists include, but are not limited to, abarelix, goserelin, and goserelin acetate.
[0121] Exemplary topoisomerase I inhibitors include, but are not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogues, 9-nitrocamptothecin, and the macromolecular camptothecin conjugate PNU-166148. Topoisomerase 11 inhibitors include, but are not limited to, anthracyclines, such as doxorubicin, daunorubicin, epirubicin, idarubicin, and nemorubicin; anthraquinones, such as mitoxantrone and losoxantrone; and podophillotoxines, such as etoposide and teniposide.
[0122] Microtubule active agents include microtubule stabilizing, microtubule destabilizing compounds, and microtubulin polymerization inhibitors including, but not limited to, taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine, vinblastine sulfate, vincristine, and vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof.
[0123] Exemplary nonlimiting alkylating agents include cyclophosphamide, ifosfamide, melphalan, and nitrosoureas, such as carmustine and lomustine.
[0124] Exemplary' nonlimiting cyclooxygenase inhibitors include Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib, rofecoxib, etoricoxib, valdecoxib, or a 5-alkyl-2-arylaminophenyl acetic acid, such as lumiracoxib.
[0125] Exemplary' nonlimiting matrix metalloproteinase inhibitors ("MMP inhibitors”) include collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, batimastat, marimastat, prinomastat, metastat, BMS-279251, BAY 12-9566, TAA211, MMI270B, and AAJ996.
[0126] Exemplary nonlimiting mTOR inhibitors include compounds that inhibit the mammalian target of rapamycin (mTOR) and possess antiproliferative activity such as sirolimus, everolimus, CCI-779, and ABT578.
[0127] Exemplary' nonlimiting antimetabolites include 5-fluorouraci I (5-FU), capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists, such as pemetrexed.
[0128] Exemplary' nonlimiting platin compounds include carboplatin, cis-platin, cisplatinum, and oxaliplatin.
[0129] Exemplary nonlimiting methionine aminopeptidase inhibitors include bengamide or a derivative thereof and PPI-2458.
[0130] Exemplary nonlimiting bisphosphonates include etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid.
[0131] Exemplary nonlimiting antiproliferative antibodies include trastuzumab, trastuzumab-DMl, cetuximab, bevacizumab, rituximab, PR064553, and 2C4. The term "antibody" is meant to include intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.
[0132] Exemplary nonlimiting heparanase inhibitors include compounds that target, decrease, or inhibit heparin sulfate degradation, such as PI-88 and OGT2115.
[0133] The term “an inhibitor of Ras oncogenic isoforms," such as H~Ras, K-Ras, or N- Ras, as used herein refers to a compound which targets, decreases, or inhibits the oncogenic activity of Ras, for example, a farnesyl transferase inhibitor, such as L-744832, DK8G557, tipifarnib, and lonafarnib.
[0134] Exemplary' nonlimiting telomerase inhibitors include compounds that target, decrease, or inhibit the activity of telomerase, such as compounds that inhibit the telomerase receptor, such as telomestatin.
[0135] Exemplary nonlimiting proteasome inhibitors include compounds that target, decrease, or inhibit the activity of the proteasome including, but not limited to, bortezomid.
[0136] The phrase "compounds used in the treatment of hematologic malignancies" as used herein includes FMS-like tyrosine kinase inhibitors, which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, I-β-D-arabinofuransylcytosine (ara-c), and bisulfan; and ALK inhibitors, which are compounds which target, decrease, or inhibit anaplastic lymphoma kinase.
[0137] Exemplary nonlimiting Fit-3 inhibitors include PKC412, midostaurin, a staurosporine derivative, SU11248, and MLN518.
[0138] Exemplary nonlimiting HSP90 inhibitors include compounds targeting, decreasing, or inhibiting the intrinsic ATPase activity of HSP90; or degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17- allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds, radicicol and HDAC inhibitors.
[0139] The phrase "a compound targeting/decreasing a protein or lipid kinase activity'; or a protein or lipid phosphatase activity; or any further anti -angiogenic compound" as used herein includes a protein tyrosine kinase and/or serine and/or threonine kinase inhibitor or lipid kinase inhibitor, such as a) a compound targeting, decreasing, or inhibiting the activity of the platelet- deri ved growth factor-receptors (PDGFR), such as a compound that targets, decreases, or inhibits the activity of PDGFR, such as an N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SUIOI, SU6668, and GFB-111 , b) a compound targeting, decreasing, or inhibiting the activity of the fibroblast growth factor-receptors (FGFR); c) a compound targeting, decreasing, or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as a compound that targets, decreases, or inhibits the activity of IGF-IR; d) a compound targeting, decreasing, or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) a compound targeting, decreasing, or inhibiting the activity of the Axl receptor tyrosine kinase family; f) a compound targeting, decreasing, or inhibiting the activity of the Ret receptor tyrosine kinase; g) a compound targeting, decreasing, or inhibiting the activity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; h) a compound targeting, decreasing, or inhibiting the activity of the c-
Kit receptor tyrosine kinases, such as imatinib; i) a compound targeting, decreasing, or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. Bcr- Abl kinase) and mutants, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib; PD180970; AG957; NSC 680410; PD173955; or dasatinib; j) a compound targeting, decreasing, or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and Ras/MAPK family members, and/or members of the cyclin-dependent kinase family (CDK), such as a staurosporine derivative disclosed in U.S. Patent No. 5,093,330, such as midostaurin; examples of further compounds include UCN- 01, safingoi, BAY 43-9006, bryostatin 1, perifosine, ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; a isochinoline compound; a farnesyl transferase inhibitor; PD184352 or QAN697, or .AT7519; k) a compound targeting, decreasing or inhibiting the activity of a protein-tyrosine kinase, such as imatinib mesylate or a tyrphostin, such as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213, Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5- dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); 1) a compound targeting, decreasing, or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as CP 358774, ZD 1839, ZM 105180; trastuzumab, cetuximab, gefitinib, erlotinib, OSI-774, CI-1033, EKB-569, GW-2016, antibodies El.l, E2.4, E2.5, E6.2, E6.4, E2. l l, E6.3 and E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives, and m) a compound targeting, decreasing, or inhibiting the activity of the c- Met receptor.
[0140] Exemplary compounds that target, decrease, or inhibit the activity of a protein or lipid phosphatase include inhibitors of phosphatase 1, phosphatase 2 A, or CDC25, such as okadaic acid or a derivative thereof.
[0141] Further anti-angiogenic compounds include compounds having another mechanism for their activity unrelated to protein or lipid kinase inhibition, e.g., thalidomide and TNP- 470.
[0142] Additional, nonlimiting, exemplary chemotherapeutic compounds, one or more of which may be used in combination with islatravir, include: daunorubicin, adriamycin, Ara-
C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, PKC412, 6- mercaptopurine (6-MP), fludarabine phosphate, octreotide, SOM230, FTY720, 6- thioguanine, cladribine, 6-mercaptopurine, pentostatin, hydroxyurea, 2-hydroxy-1H- isoindole-1, 3-dione derivatives, l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, l-(4-chloroanilino)-4-(4- pyridylmethyl)phthalazine succinate, angiostatin, endostatin, anthranilic acid amides, ZD4190, ZD6474, SU5416, SU6668, bevacizumab, rhuMAb, rhuFab, macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, RPI 4610, bevacizumab, porfimer sodium, anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortex clone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, dexamethasone, fluocinolone, a plant alkaloid, a hormonal compound and/or antagonist, a biological response modifier, such as a lymphokine or interferon, an antisense oligonucleotide or oligonucleotide derivative, shRNA, and siRNA.
[0143] Other examples of second therapeutic agents, one or more of which islatravir also can be combined, include, but are not limited to: a treatment for Alzheimer's Disease, such as donepezil and rivastigmine, a treatment for Parkinson's Disease, such as L- DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; an agent for treating multiple sclerosis (MS) such as beta interferon (e.g., AVONEX® and REBIF®), glatiramer acetate, and mitoxantrone; a treatment for asthma, such as albuterol and montelukast; an agent for treating schizophrenia, such as zyprexa, risperdal, seroquel, and haloperidol; an anti-inflammatory agent, such as a corticosteroid, a TNF blocker, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; an immunomodulatory agent, including immunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, an interferon, a corticosteroid, cyclophosphamide, azathioprine, and sulfasalazine; a neurotrophic factor, such as an acetylcholinesterase inhibitor, an MAO inhibitor, an interferon, an anticonvulsant, an ion channel blocker, riluzole, or an anti -Parkinson's agent; an agent for treating cardiovascular disease, such as a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, a calcium channel blocker, or a statin, an agent for treating liver disease, such as a corticosteroid, cholestyramine, an interferon, and an anti-viral agent; an agent for treating blood disorders, such as a corticosteroid, an anti-leukemic agent, or a growth factor; or an agent for treating immunodeficiency disorders, such as gamma globulin.
[0144] In another embodiment, the second therapeutically active agent is an immune checkpoint inhibitor. Examples of immune checkpoint inhibitors include PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG3 inhibitors, TIM3 inhibitors, cd47 inhibitors, and B7-H1 inhibitors. Thus, in one embodiment, islatravir is administered in combination with an immune checkpoint inhibitor is selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a TIM3 inhibitor, and a cd47 inhibitor,
[0145] In another embodiment, the immune checkpoint inhibitor is a programmed cell death (PD-1) inhibitor. PD-1 is a T-cell coinhibitory receptor that plays a pivotal role in the ability of tumor cells to evade the host's immune system. Blockage of interactions between PD-1 and PD-LI, a ligand of PD-1, enhances immune function and mediates antitumor activity. Examples of PD-1 inhibitors include antibodies that specifically bind to PD-1. Particular anti-PD-1 antibodies include, but are not limited to nivolumab, pembrolizumab, STI-A1014, and pidilzumab. For a general discussion of the availability, methods of production, mechanism of action, and clinical studies of anti-PD-1 antibodies, see U.S. 2013/0309250, U.S. 6,808,710, U.S. 7,595,048, U.S. 8,008,449, U.S. 8,728,474, U.S. 8,779,105, U.S. 8,952,136, U.S. 8,900,587, U.S. 9,073,994, U.S. 9,084,776, andNaido et al., British Journal of Cancer 777/2214-19 (2014).
[0146] In another embodiment, the immune checkpoint inhibitor is a PD-LI (also known as B7-H1 or CD274) inhibitor. Examples of PD-LI inhibitors include antibodies that specifically bind to PD-LI. Particular anti-PD-L1 antibodies include, but are not limited to, avelumab, atezolizumab, durvalumab, and BMS-936559. For a general discussion of the availability, methods of production, mechanism of action, and clinical studies, see U.S. 8,217,149, U.S. 2014/0341917, U.S. 2013/0071403, WO 2015036499, and Naido et al., British Journal of Cancer 111:22.14-19 (2014).
[0147] In another embodiment, the immune checkpoint inhibitor is a CTLA-4 inhibitor. CTLA-4, also known as cytotoxic T-lymphocyte antigen 4, is a protein receptor that downregulates the immune system. CTLA-4 is characterized as a "brake" that binds costimulatory molecules on antigen-presenting cells, which prevents interaction with CD28 on T cells and also generates an overtly inhibitory signal that constrains T cell activation. Examples of CTLA-4 inhibitors include antibodies that specifically bind to CTLA-4. Particular anti-CTLA-4 antibodies include, but are not limited to, ipilimumab and
tremelimumab. For a general discussion of the availability, methods of production, mechanism of action, and clinical studies, see U.S. 6,984,720, U.S. 6,207,156, and Naido et al. , British Journal of Cancer 111 : 2214- 19 (2014).
[0148] In another embodiment, the immune checkpoint inhibitor is a LAG3 inhibitor. LAG3, Lymphocyte Activation Gene 3, is a negative co-simulatory receptor that modulates T cell homeostatis, proliferation, and activation. In addition, LAG3 has been reported to participate in regulatory T cells (Tregs) suppressive function. A large proportion of LAG3 molecules are retained in the cell close to the microtubule-organizing center, and only induced following antigen specific T cell activation. U.S. 2014/0286935. Examples of LAG3 inhibitors include antibodies that specifically bind to LAG3. Particular anti-LAG3 antibodies include, but are not limited to, GSK2831781. For a general discussion of the availability, methods of production, mechanism of action, and studies, see, U.S. 2011/0150892, U.S. 2014/0093511, U.S. 20150259420, and Huang et al., Immunity 21 :503-13 (2004).
[0149] In another embodiment, the immune checkpoint inhibitor is a TIM3 inhibitor. TIM3, T-cell immunoglobulin and mucin domain 3, is an immune checkpoint receptor that, functions to limit the duration and magnitude of TH1 and TC1 T-cell responses. The TIM3 pathway is considered a target for anticancer immunotherapy due to its expression on dysfunctional CD8+T cells and Tregs, which are two reported immune cell populations that constitute immunosuppression in tumor tissue. Anderson, Cancer Immunology’ Research 2:393-98 (2014). Examples of TIM3 inhibitors include antibodies that specifically bind to TIM3. For a general discussion of the availability, methods of production, mechanism of action, and studies of TIM3 inhibitors, see U.S. 20150225457, U.S. 20130022623, U.S. 8,522,156, Ngiow et al., Cancer Res 71: 6567-71 (2011), Ngiow, et al.. Cancer Res 71.’3540-51 (2011), and Anderson, Cancer Immunology Res 2:393 -98 (2014).
[0150] In another embodiment, the immune checkpoint inhibitor is a cd47 inhibitor. See Unanue, E.R., PNAS 110: 10886-87 (2013).
[0151] The term "antibody" is meant to include intact monoclonal antibodies, polyclonal antibodies, multi specific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity. In another embodiment, "antibody" is meant to include soluble receptors that do not possess the
Fc portion of the antibody. In one embodiment, the antibodies are humanized monoclonal antibodies and fragments thereof made by means of recombinant genetic engineering.
[0152] Another class of immune checkpoint inhibitors include polypeptides that bind to and block PD-1 receptors on T-cells without triggering inhibitor signal transduction. Such peptides include B7-DC polypeptides, B7-H1 polypeptides, B7-1 polypeptides and B7-2 polypeptides, and soluble fragments thereof, as disclosed in U.S. Pat. 8,114,845.
[0153] Another class of immune checkpoint inhibitors include compounds with peptide moieties that inhibit PD-1 signaling. Examples of such compounds are disclosed in U.S. Pat. 8,907,053.
[0154] Another class of immune checkpoint inhibitors include inhibitors of certain metabolic enzymes, such as indoleamine 2,3 dioxygenase (IDO), which is expressed by infiltrating myeloid cells and tumor cells. The 11)0 enzyme inhibits immune responses by depleting amino acids that are necessary for anabolic functions in T cells or through the synthesis of particular natural ligands for cytosolic receptors that are able to alter lymphocyte functions. Pardoll, Nature Reviews. Cancer 12:252-64 (2012); Lob, Cancer Immunol Immimother 58;153-57 (2009). Particular IDO blocking agents include, but are not limited to levo- 1 -methyl typtophan (L-1MT) and 1 -methyl -tryptophan (1MT). Qian et al., Cancer Res 69: 5498-504 (2009); and Lob et al., Cancer Immunol Immunother 58: \53- 7 (2009).
[0155] In one embodiment, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, STI-Al l 10, avelumab, atezolizumab, durvalumab, STI-A1014, ipilimumab, tremelimumab, GSK2831781, BMS-936559 or MED14736.
[0156] When the RTI is an FDA approved drug, the RTI may be administered in therapeutically effective amounts that are approved for therapeutic use. In other embodiments, the amounts effective can be determined with no more than routine experimentation. For example, amounts effective may range from about 1 ng/kg to about 200 mg/kg, about 1 μg/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg. The dosage of a composition can be at any dosage including, but not limited to, about 1 μg/kg. The dosage of a composition may be at any dosage including, but not limited to, about 1 μg/kg, about 10 μg/kg, about 25 μg/kg, about 50 μg/kg, about 75 μg/kg, about 100 μg/kg, about 125 μg/kg, about 150 μg/kg, about 175 μg/kg, about 200 μg/kg, about 225 μg/kg, about 250 μg/kg, about 275 μg/kg, about 300 μg/kg, about 325 , μg/kg, about 350 μg/kg,
about 375 μg/kg, about 400 μg/kg, about 425 μg/kg, about 450 μg/kg, about 475 μg/kg, about 500 μg/kg, about 525 μg/kg, about 550 μg/kg, about 575 μg/kg, about 600 μg/kg, about 625 μg/kg, about 650 μg/kg, about 675 μg/kg, about 700 μg/kg, about 725 μg/kg, about 750 μg/kg, about 775 μg/kg, about 800 μg/kg, about 825 μg/kg, about 850 μg/kg, about 875 μg/kg, about 900 μg/kg, about 925 μg/kg, about 950 μg/kg, about 975 μg/kg, about I mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg, or more. In other embodiments, the dosage is 1 mg-500 mg. In some embodiments, the dosage is 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 mg. These doses may be unitary or divided and may be administered one or more times per day. The above dosages are exemplary of the average case, but there can be individual instances in which higher or lower dosages are merited, and such are within the scope of this disclosure. In practice, the physician determines therapeutically effective amounts and the actual dosing regimen that is most suitable for an individual subject, which can vary with the age, weight, and response of the particular subject.
[0157] The RTI may be administered once, twice or three times per day for 1 day to the end of life, or for 1 day to 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more years, or until the RTI causes unacceptable side effects or is no longer useful.
[0158] In some embodiments, when the method is a method for the treatment of breast cancer, the at least one second therapeutic agent is Soltamox® (tamoxifen), Arimidex® (anastrozole), Femara® (letrozole), Aromasin® (exemestane), Herceptin® (trastuzumab), Abraxane® (paclitaxel), Cytoxan® (cyclophosphamide), Taxol® (paclitaxel), Afmitor® (everolimus), Taxotere® (docetaxel), Xeloda® (capeci tabine), Trexall® (methotrexate), Faslodex (fulvestrant), Adriamycin® (doxorubicin), Peijeta® (pertuzumab), Gemzar (gemcitabine), Tykerb® (lapatinib), Adrucil® (fluorouracil), Ibrance® (palbociclib), Verzenio® (abemaciclib), Fareston® (toremifene), Halaven® (eribulin), Menest, Kadcyla® (ado-trastuzumab emtransine), Androxy® (fluoxymesterone), Avastin® (bevacizumab), esterified estrogens, Herzuma® (trastuzumab), Ixempra® (ixabepilone), Kanjinti® (trastuzumab), Kisqali® (ribociclib), Ogivri® (trastuzumab), Ontruzant® (trastuzumab), Tepadina® (thiotepa), Trazimera® (trastuzumab), Velban® (vinblastine),
Piqray® (alpelisib), Tecentriq® (atezolizumab), Enhertu® (fam-trastuzumab deruxtecan), Herceptin, Hylecta™ (hyaluronidase/trastuzumab), Infugem® (gemcitabine), Kisqali® Femara® Co-Pack (ribociclib and letrozole), Talzenna® (talazoparib), Trodelvy® (sacituzumab) or Tukysa™ (tukatinib).
[0159] In some embodiments, when the method is a method for the treatment of colon cancer, the at least one second therapeutic agent is Xeloda® (capecitabine), Eloxatin® (oxaliplatin), fluorouracil, Avastin® (bevacizumab), leucovorin, Camptosar® (irinotecan), Stivarga® (regorafenib), Erbitux® (cetuximab), Vectibix® (panitumumab), Lonsurf® (tipiracil/trifluridine), Zaltrap® (ziv-aflibercept), Betaseron® (interferon beta-lb), Fusilev® (levoleucovorin), Wellcocorin® (methotrexate), Keytruda® (pembrolizumab), Mvasi® (bevacizumab-awwb), Cyramza® (ramucirumab), Yervoy® (ipilmumab), Opdivo® (nivolumab), Braftovi® (encorafenib), Khapzory® (levoleucovorin) or Zirabev® (b evacizumab -b vzr) .
[0160] In some embodiments, when the method is a method for the treatment of lung cancer, the at least one second therapeutic agent is Etopophos® (etoposide), Hycamtin® (topotecan), VePesid® (etoposide), Toposar® (etoposide), Opdivo® (nivolumab), Keytruda® (pembrolizumab), Tecentriq® (atezolizumab), Imfmizi® (durvalumab), methotrexate, cyclophosphamide, Carboplatin, Cisplatin, docetaxel, Gemcitabine, Irinotecan, Paclitaxel, Pemetrexed, Vinblastine, or Vinorelbine.
[0161] In some embodiments, when the method is a method for the treatment of pancreatic ductal cancer, the at least one second therapeutic agent is Gemzar® (Gemcitabine), fluorouracil, Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (irinotecan), bevacizumab, cetuximab, Infugem® (gemcitabine) or Lynparza® (olaparib).
[0162] In some embodiments, when the method is a method for the treatment of head and neck cancer, the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
[0163] In some embodiments, when the method is a method for the treatment of prostate cancer the at least one second therapeutic agent is Suprefact® (buserelin), Firmagon® (degarelix), Zoladex® (goserelin), Vanias® (histrelin), Eligard® (leuprolide), Orgovyx®
(relugolix), Trelstar® (triptorelin), Casodex® (bicalutamide), Eulexin® (flutamide), Nilandron® (nilutamide), Zytiga® (biraterone acetate), Erleada® (apalutamide), or Xtandi ® (enzal utami de) .
[0164] In some embodiments, the at least one second therapeutic agent is a STING agonist. Exemplary STING agonists include E7766, MIW815, SNX281, and TAK-676. See, e.g., Aval et al., Journal of Clinical Medicine 9:3323 (2020); Su et al., Theranostics 9:7759- 7771 (2019).
[0165] The RTI and/or DDR enzyme inhibitor and at least one second therapeutic agent may be administered separately or together as part of a unitary pharmaceutical composition.
[0166] In some embodiments, the patient is (a) not infected with the HIV virus, (b) not suspected of being infected with the HIV virus, (c) not being treated for the HIV virus, and/or (d) not being treated to prevent the HIV virus.
[0167] The terms "patient" and "subject" as used herein are synonymous terms referring to any human or animal that is in need of or might benefit from administration of a RTI and/or DDR enzyme inhibitor for treating cancer. Foremost among such subjects are mammals, e.g., humans, although the methods and compositions provided herein are not intended to be so limited. Other subjects include veterinary animals, e.g., cows, sheep, pigs, horses, dogs, cats and the like. In one embodiment, the subject is a human. In one embodiment, the subject is an animal.
Salts, Pharmaceutical Compositions, and Kits
[0168] The methods of the present disclosure can be accomplished by administering RTI as the neat compound or as a pharmaceutical composition.
[0169] Administration of a pharmaceutical composition, or a neat RTI and/or DDR enzyme inhibitor can be performed before, during, or after the clinical diagnosis of the cancer. Typically, the pharmaceutical compositions are sterile, and contain no toxic, carcinogenic, or mutagenic compounds that would cause an adverse reaction when administered.
[0170] Further provided are kits comprising the RTI and/or DDR enzyme inhibitor and, optionally, at least one second therapeutic agent useful for the treatment of cancer associated, packaged separately or together, and an insert having instructions for using these active agents. In one embodiment, the RTI and/or DDR enzyme inhibitor is packaged alone together with instructions to administered together with the at least one second therapeutic agent. The RTI and/or DDR enzyme inhibitor and the at least one second
therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect. In addition, the RTI and the at least one second therapeutic agent can be administered from a single composition or two separate compositions.
[0171] The second therapeutic agent is administered in an amount to provide its desired therapeutic effect. The effective dosage range for each optional therapeutic agent is known in the art, and the optional therapeutic agent is administered to an individual in need thereof within such established ranges.
[0172] The present disclosure encompasses the preparation and use of salts of a RTI and/or DDR enzyme inhibitor. As used herein, a "pharmaceutically acceptable salt" refers to salts or zwitterionic forms of a RTI and/or DDR enzyme inhibitor. Salts of a RTI and/or DDR enzyme inhibitor can be prepared during the final isolation and purification of the compound or separately by reacting the compound with a suitable acid. The pharmaceutically acceptable salts of a RTI and/or DDR enzyme inhibitor can be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Non-limiting examples of salts of a RTI and/or DDR enzyme inhibitor include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerol phsphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesityl enesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedi sulfonate, benzene sulfonate, and p-toluenesulfonate salts.
[0173] The present disclosure encompasses the preparation and use of solvates of a RTI and/or DDR enzyme inhibitor. Solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents. The term "solvate" as used herein is a combination, physical association and/or solvation of a compound with a solvent molecule such as, e.g. a
- disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound is about 2: 1, about 1 : 1 or about 1 :2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution- phase and isolatable solvates. A RTI and/or DDR enzyme inhibitor can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, and ethanol. It is intended that the disclosure includes both solvated and unsolvated forms of a RTI. One type of solvate is a hydrate. A "hydrate" relates to a particular subgroup of solvates where the solvent molecule is water. Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M. Caira et al, J Pharmaceut. Sci., 93(3):601-61 1 (2004), which describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparation of solvates, hemisolvates, hydrates, and the like are described by E.C. van Tender et al., AAPS Pharm. Sci. Tech., 5(1): Article 12 (2004), and A.L. Bingham et al., Chem. Commim. 603- 604 (2001). A typical, non-limiting, process of preparing a solvate would involve dissolving a RTI in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvate in a cry sial of the solvate.
[0174] The RTI and/or DDR enzyme inhibitor is typically are administered in admixture with a pharmaceutical carrier to give a pharmaceutical composition selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present disclosure are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the RTI and/or DDR enzyme inhibitor.
[0175] These pharmaceutical compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen. When a therapeutically effective amount of a RTI and/or DDR
enzyme inhibitor is administered orally, the composition typically is in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition additionally can contain a solid carrier, such as a gelatin or an adjuvant. The tablet, capsule, and powder contain about 0.01% to about 95%, and preferably from about 1% to about 50%, of a RTI and/or DDR enzyme inhibitor, or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof. When administered in liquid form, a liquid carrier, such as water, petroleum, or oils of animal or plant origin, can be added. The liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solutions, or glycols. When administered in liquid form, the composition contains about 0.1 % to about 90%, and preferably about 1% to about 50%, by weight, of a RTI and/or DDR enzyme inhibitor.
[0176] When a therapeutically effective amount of a RTI and/or DDR enzyme inhibitor is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains, an isotonic vehicle.
[0177] A RTI and/or DDR enzyme inhibitor can be readily combined with pharmaceutically acceptable carriers well-known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995. Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained by adding a RTI and/or DDR enzyme inhibitor to a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrating agents can be added.
[0178] A RTI and/or DDR enzyme inhibitor can be formulated for parenteral administration by injection, e.g,, by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative. The compositions can take such forms as
suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.
[0179] Pharmaceutical compositions for parenteral administration include aqueous solutions of the RTI and/or DDR enzyme inhibitor in water-soluble form. Additionally, suspensions of a compound of a RTI can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension. Optionally, the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions. Alternatively, a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
[0180] In particular, a RTI and/or DDR enzyme inhibitor can be administered orally in the form of tablets containing excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents. A RTI and/or DDR enzyme inhibitor also can be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily. For parenteral administration, a RTI and/or DDR enzyme inhibitor typically used in the form of a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.
Biomarkers
[0181] The term "biomarker" as used herein refers to any biological compound, such as a gene, a protein, a fragment of a protein, a peptide, a polypeptide, a nucleic acid, etc., or chromosome abnormality, such as a chromosome translocation, that can be detected and/or quantified in a subject in vivo or in a biological sample obtained from a subject. A biomarker can be the entire intact molecule, or it can be a portion or fragment thereof. In one embodiment, the expression level of the biomarker is measured. The expression level of the biomarker can be measured, for example, by detecting the protein or RNA, e.g., mRNA, level of the biomarker. In some embodiments, portions or fragments of biomarkers can be detected or measured, for example, by an antibody or other specific binding agent.
In some embodiments, a measurable aspect of the biomarker is associated with a given state of the subject, such as the subject's age. For biomarkers that are detected at the protein or RNA level, such measurable aspects may include, for example, the presence, absence, or concentration, i.e., expression level, of the biomarker in the subject, or biological sample obtained from the subject. For biomarkers that are detected at the nucleic acid level, such measurable aspects may include, for example, allelic versions of the biomarker or type, rate, and/or degree of mutation of the biomarker, also referred to herein as mutation status. [0182] For biomarkers that are detected based on expression level of protein or RNA, expression level measured between different phenotypic statuses can be considered different, for example, if the mean or median expression level of the biomarker in the different groups is calculated to be statistically significant. Common tests for statistical significance include, among others, t-test, ANOVA, Kruskal -Wall is, Wilcoxon, Mann- Whitney, Significance Analysis of Microarrays, odds ratio, etc. Biomarkers, alone or in combination, provide measures of relative likelihood that a subject belongs to one phenotypic status or another. Therefore, they are useful, inter alia, as markers for disease and as indicators that particular therapeutic treatment regimens will likely result in beneficial patient outcomes. The term "overexpression" indicates that the expression level of the biomarker in the subject having a disease, condition, or disorder is amplified, e.g., above the mean or median expression level of the biomarker in, e.g., a normal undiseased subject.
[0183] Biomarkers include, but are not limited to, DDR enzymes, e.g., Pol η Pol μ, or Pol θ, or genes, e.g., POLE, POLM, or POLQ. In one embodiment, the measurable aspect of the biomarker is its expression status. In another embodiment, the measurable aspect of the biomarker is elevated levels, e.g., over express! on, of the biomarker. In one embodiment, the measurable aspect of the biomarker is its mutation status.
[0184] In one embodiment, the biomarker is Pol θ expression which is differentially present in a subject of one phenotypic status, e.g., a subject having cancer as compared with another phenotypic status, e.g., a normal undiseased subject or a subject having a cancer without overexpression of Pol θ. In one embodiment, the biomarker is overexpression of Pol θ in cancer cells.
[0185] In another embodiment, the biomarker is Pol μ expression which is differentially present in a subject of one phenotypic status, as compared with another phenotypic status.
In one embodiment, the biomarker is overexpression of Pol η, e.g., in cancer cells. In one embodiment, the biomarker is overexpression of POLE, e.g., in cancer cells.
[0186] In another embodiment, the biomarker is Pol μ expression which is differentially present in a subject of one phenotypic status as compared with another phenotypic status. In one embodiment, the biomarker is overexpression of Pol μ, e.g., in cancer cells. In one embodiment, the biomarker is overexpression of POLM, e.g., in cancer cells.
[0187] In one embodiment, the biomarker is BR.CA1 expression which is differentially present in a subject of one phenotypic status, e.g., a subject having cancer as compared with another phenotypic status, e.g., a normal undiseased subject or a subject having a cancer without overexpression of BRCA1 . In one embodiment, the biomarker is overexpression of BRCA1 in cancer cells.
[0188] In one embodiment, the biomarker is BRCA2 expression which is differentially present in a subject of one phenotypic status, e.g., a subject having cancer as compared with another phenotypic status, e.g., a normal undiseased subject or a subject having a cancer without overexpression of BRCA2. In one embodiment, the biomarker is overexpression of BRCAl in cancer cells.
[0189] In one embodiment, the biomarker is Pol θ, Pol η or Pol μ expression which is differentially present in a subject of one phenotypic status, e.g., a subject after administration of a Compound of the Disclosure, as compared with another phenotypic status, e.g., a normal undiseased subject or a subject before administration of a Compound of the Disclosure. In some embodiments, the biomarker is descressed expression of Pol θ, Pol η, or Pol μ caused by administration of a Compound of the Disclosure to a subject.
[0190] Biomarker standards can be predetermined, determined concurrently, or determined after a biological sample is obtained from the subject. Biomarker standards for use with the methods described herein can, for example, include data from samples from subjects without cancer and/or data from samples from subjects with a cancer. Comparisons can be made to establish predetermined threshold biomarker standards for different classes of subjects, e.g., diseased vs. non-diseased subjects. The standards can be run in the same assay or can be known standards from a previous assay.
[0191] A biomarker is differentially present between different phenotypic status groups if the mean or median expression or mutation levels of the biomarker is calculated to be
different, i.e., higher or lower, between the groups. Thus, biomarkers provide an indication that a subject, e.g., a subject having cancer, belongs to one phenotypic status or another.
[0192] In addition to individual biological compounds, e.g., Pol θ, the term "biomarker" as used herein is meant to include groups, sets, or arrays of multiple biological compounds. The term "biomarker" may comprise one, two, three, four, five, six, seven, eight, nine, ten, fifteen, twenty, twenty five, thirty, or more, biological compounds. In embodiment, the biomarker comprises one, two, or three biological compounds.
[0193] The determination of the expression level or mutation status of a biomarker in a subject can be performed using any of the many methods known in the art. Any method known in the art for quantitating specific proteins and/or detecting biomarker expression, e.g., Pol θ, Pol η, or Pol μ expression, and/or or the expression or mutation levels of any other biomarker(s) in a patient or a biological sample may be used in the methods of the disclosure. Examples include, but are not limited to, PCR (polymerase chain reaction), or RT-PCR, flow cytometry. Northern blot, Western blot, immunoassays, e.g., ELISA (enzyme linked immunosorbent assay), RIA (radioimmunoassay), SimoaTM, gene chip analysis of RNA expression, immunohistochemistry, immunofluorescence, or massspectroscopy. See, e.g., Slagle et al. Cancer 83: 1401 (1998). Certain embodiments of the disclosure include methods wherein biomarker RNA expression (transcription) is determined. Other embodiments of the disclosure include methods wherein protein expression in the biological sample is determined. See, e.g., Harlow et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, (1988); Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons, New York 3rd Edition, (1995); Kamel and Al-Amodi, Genomics Proteomics Bioinformatics 15:220-235 (2017). For northern blot or RT-PCR analysis, RNA is isolated from tissue sample using RNAse free techniques. Such techniques are commonly known in the art.
[0194] In one embodiment of the disclosure, a biological sample is obtained from the subject and the biological sample is assayed for determination of a biomarker expression or mutation status. In some embodiments, the biological sample is blood from the subject. In some embodiments, the biological sampl e is the cancer tissue or cells of the patient,
[0195] In another embodiment of the disclosure, Northern blot analysis of biomarker transcription in a tumor cell sample is performed. Northern analysis is a standard method for detection and/or quantitation of mRNA levels in a sample. Initially, RNA is isolated
from a sample to be assayed using Northern biot analysis, In the analysis, the RNA samples are first separated by size via electrophoresis in an agarose gel under denaturing conditions. The RNA is then transferred to a membrane, crosslinked and hybridized with a labeled probe. Typically, Northern hybridization involves polymerizing radiolabeled or nonisotopically labeled DNA, in vitro, or generation of oligonucleotides as hybridization probes. Typically, the membrane holding the RNA sample is prehybridized or blocked prior to probe hybridization to prevent the probe from coating the membrane and, thus, to reduce non-specific background signal. After hybridization, typically, unhybridized probe is removed by washing in several changes of buffer. Stringency of the wash and hybridization conditions can be designed, selected and implemented by any practitioner of ordinary skill in the art. Detection is accomplished using detectably labeled probes and a suitable detection method. Radiolabeled and non-radiolabled probes and their use are well known in the art. The presence and or relative levels of expression of the biomarker being assayed can be quantified using, for example, densitometry.
[0196] In another embodiment, biomarker expression and/or mutation status is determined using RT-PCR. RT-PCR allows detection of the progress of a PCR amplification of a target gene in real time. Design of the primers and probes required to detect expression and/or mutation status of a biomarker of the disclosure is within the skill of a practitioner of ordinary skill in the art.. RT-PCR can be used, for example, to determine the level of RNA encoding a biomarker of the disclosure in a tissue sample. In an embodiment of the disclosure, RNA from the biological sample is isolated, under RNAse free conditions, than converted to DNA by treatment with reverse transcriptase. Methods for reverse transcriptase conversion of RNA to DNA are well known in the art.. A description of PCR is provided in the following references: Mullis et al., Cold Spring Harbor Symp. Quant. Biol. 51 :263 (1986); EP 50,424; EP 84,796; EP 258,017; EP 237,362; EP 201,184; U.S. Patent Nos. 4,683,202; 4,582,788; 4,683,194.
[0197] RT-PCR probes depend on the 5'-3‘ nuclease activity of the DNA polymerase used for PCR to hydrolyze an oligonucleotide that is hybridized to the target amplicon (biomarker gene). RT-PCR probes are oligonucleotides that have a fluorescent reporter dye attached to the 5' end and a quencher moiety coupled to the 3' end (or vice versa). These probes are designed to hybridize to an internal region of a PCR product. In the unhybridized state, the proximity of the fluor and the quench molecules prevents the
detection of fluorescent signal from the probe. During PCR amplification, when the polymerase replicates a template on which an RT-PCR probe is bound, the 5'-3‘ nuclease activity of the polymerase cleaves the probe. This decouples the fluorescent and quenching dyes and FRET no longer occurs. Thus, fluorescence increases in each cycle, in a manner proportional to the amount of probe cleavage. Fluorescence signal emitted from the reaction can be measured or followed over time using equipment which is commercially available using routine and conventional techniques.
[0198] In another embodiment of the disclosure, expression of proteins encoded by biomarkers are detected by western blot analysis. A western blot (also known as an immunoblot) is a method for protein detection in a given sample of tissue homogenate or extract. It uses gel electrophoresis to separate denatured proteins by mass. The proteins are then transferred out of the gel and onto a membrane (e.g., nitrocellulose or poly vinylidene fluoride (PVDF)), where they are detected using a primary antibody that specifically bind to the protein. The bound antibody can then detected by a secondary' antibody that is conjugated with a detectable label (e.g., biotin, horseradish peroxidase or alkaline phosphatase). Detection of the secondary label signal indicates the presence of the protein.
[0199] In another embodiment of the disclosure, the expression of a protein encoded by a biomarker is detected by enzyme-linked immunosorbent assay (ELISA). In one embodiment of the disclosure, "sandwich ELISA" comprises coating a plate with a capture antibody; adding sample wherein any antigen present binds to the capture antibody; adding a detecting antibody which also binds the antigen, adding an enzyme-linked secondary antibody which binds to detecting antibody; and adding substrate which is converted by an enzyme on the secondary antibody to a detectable form. Detection of the signal from the secondary antibody indicates presence of the biomarker antigen protein.
[0200] In one embodiment, present disclosure provides methods of treating a subject having cancer, the method comprising: (a) determining whether a biomarker, e.g., overexpression of Pol θ, Pol η, or Pol μ, is present or absent in a biological sample taken from the subject; and (b) administering an RTI and/or DDR enzyme inhibitor to the subject if the biomarker is present in the biological sample.
[0201] In another embodiment, the present disclosure provides a method of identifying whether a subject having cancer as a candidate for treatment with a RTI and/or DDR enzyme inhibitor, the method comprising: (a) determining whether a biomarker, e.g..
overexpression of POLQ, is present or absent in a biological sample taken from the subject; and (b) identifying the subject as being a candidate for treatment if the biomarker is present; or (c) identifying the subject as not being a candidate for treatment if the biomarker is absent.
[0202] In another embodiment, the present disclosure provides a method of predicting treatment outcome in a subject having cancer, the method comprising determining whether a bi ©marker, e.g., overexpression of Pol θ, Pol rp or Pol μ, is present or absent in a biological sample taken from the subject, wherein (a) the presence of the biomarker in the biological sample indicates that administering a RTI and/or DDR enzyme inhibitor to the subject will likely cause a favorable therapeutic response; and (b) the absence of the biomarker in the biological sample indicates that administering a RTI and/or DDR enzyme inhibitor to the subject will likely cause an unfavorable therapeutic response.
[0203] In another embodiment, the present disclosure provides a method, comprising administering a therapeutically effective amount of a RTI and/or DDR enzyme inhibitor to a subject in need thereof, wherein: (a) the subject has cancer; and (b) the cancer is characterized as having a biomarker, e.g., overexpression of one or more DNA damage repair enzymes, e.g., overexpression of Pol 6, Pol μ, or Pol μ.
[0204] In another embodiment, the present disclosure provides a method of treating a subject having cancer, the method comprising:
[0205] (a) determining whether an overexpression of one or more DNA damage repair enzymes, e.g., Pol 6, Pol μ, and/or Pol μ, is present, or absent in a biological sample taken from the subject; and
[0206] (b) administering a therapeutically effective amount a Compound of the Disclosure to the subject if an overexpression of one or more DNA damage repair enzymes is present in the biological sample.
[0207] In another embodiment, the present disclosure provides a method of identifying whether a subject having cancer as a candidate for treatment with a Compound of the Disclosure, the method comprising:
[0208] (a) determining whether an overexpression of one or more DNA damage repair enzymes, e.g., Pol θ, Pol μ, and/or Pol μ, is present, or absent in a biological sample taken from the subject; and
[0209] (b) identifying the subject as being a candidate for treatment if an overexpression of one or more DNA damage repair enzymes is present; or
[0210] (c) identifying the subject as not being a candidate for treatment if overexpression of one or more DNA damage repair enzymes is absent.
[0211] In another embodiment, the present disclosure provides a method of predicting treatment outcome in a subject having cancer, the method comprising determining whether an overexpression of one or more DNA damage repair enzymes, e.g., Pol θ, Pol η, and/or Pol μ, is present or absent in a biological sample taken from the subject, wherein:
[0212] (a) the presence of an overexpression of one or more DNA damage repair enzymes in the biological sample indicates that administering a Compound of the Disclosure to the subject will likely cause a favorable therapeutic response; and
[0213] (b) the absence of an overexpression of one or more DNA damage repair enzymes in the biological sample indicates that administering a Compound of the Disclosure to the subject will likely cause an unfavorable therapeutic response.
[0214] In another embodiment, the present disclosure provides a Compound of the Disclosure for use in treating a subject having cancer, wherein;
[0215] (a) the expression level of a biomarker, e.g., one or more DNA damage repair enzymes, e.g., Pol 6, Pol μ, and/or Pol μ, in a biological sample taken from the subject is determined; and
[0216] (b) a therapeutically effective amount the Compound of the Disclosure is to be administered to the subject if there is an overexpression the of one or more biomarkers in the biological sample.
[0217] In another embodiment, the present disclosure provides the use of a Compound of the Disclosure in the manufacture of a medicament for treating a subject having cancer, wherein:
[0218] (a) the expression level of a biomarker, e.g., one or more DNA damage repair enzymes, e.g., Pol θ, Pol η and/or Pol μ, is determined in a biological sample taken from the subject; and
[0219] (b) a therapeutically effective amount the Compound of the Disclosure is to be administered to the subject if there is an overexpression of the one or more biomarkers in the biological sample.
Particular Embodiments
[0220] The present disclosure provides the following particular embodiments. A, DNA damage repair enzyme inhibitors for treating cancer.
[0221] Embodiment 1. A method for treating cancer in subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Table 3 to the subject.
[0222] Embodiment 2. The method of Embodiment 1, wherein the compound of Table 3 is 2-amino-9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-
(hydroxymethyl)tetrahydrofuran-2-yl)- 1 ,9-dihy dro-6H-purin-6~one; 4-amino- 1 -
((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-y])-5- fluoropyrimidin-2(lH)-one; or 4-amino-l”((2R,4S,5R)-5-ethynyl-4-hydroxy-5” (hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(lH)-one.
[0223] Embodiment 3. The method of Embodiment 1, wherein the compound of Table 3 is (2R,3 S,5R)-5-(4-amino-2-oxopyrimidin- 1 (2H)-yl)-3-hydroxy-2-
(hydroxymethyl)tetrahydrofuran-2-carbonitrile; 4-amino-1-((2R,4S,5R)-4-hydroxy-5- (hydroxymethyl)-5-methyltetrahydrofuran-2-yl)pyrimidin-2(1H)-one; or 4-amino-1- ((2R,4S,5R)-5-ethyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(lH)- one.
[0224] Embodiment 4. The method of Embodiment 1, wherein the compound of Table 3 is (2R,3S,5R)-5-(2,6-diamino-9H-purin-9-yl)-2-(hydroxymethyl)-2- vinyltetrahydrofuran-3-ol; (2R,3S,5R)-5-(2,6-di amino- 9H-purin-9-yl)-2-ethyl-2-
(hydroxymethyl)tetrahydrofuran-3-ol; or l-((2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione.
[0225] Embodiment 5. The method of any one of Embodiments 1-4, wh erein the cancer is breast cancer, colon cancer, lung cancer, pancreatic ductal cancer, prostate cancer, ovarian cancer, or head and neck cancer.
[0226] Embodiment 6. The method of Embodiment 5, wherein the cancer is breast cancer.
[0227] Embodiment 7. The method of Embodiment 5, wherein the cancer is colon cancer.
[0228] Embodiment 8. The method of Embodiment 5, wherein the cancer is lung cancer.
[0229] Embodiment 9, The method of Embodiment 5, wherein the cancer is pancreatic ductal cancer.
[0230] Embodiment 10. The method of Embodiment 5, wherein the cancer is prostate cancer.
[0231] Embodiment 11. The method of Embodiment 5, wherein the prostate cancer is high-risk localized prostate cancer.
[0232] Embodiment 12. The method of Embodiment 5, wherein the cancer is ovarian cancer.
[0233] Embodiment 13. The method of Embodiment 5, wherein the cancer is head and neck cancer.
[0234] Embodiment 14. The method of any one of Embodiments 1-5, wherein the subject has prostate cancer and the compound of Table 3 is administered as an adjuvant therapy.
[0235] Embodiment 15. The method of any one of Embodiments 1-5, wherein the subject has prostate cancer and the compound of Table 3 is administered as a neoadjuvant therapy.
[0236] Embodiment 16. The method of any one of Embodiments 1-15 further comprising administering a therapeutically effective amount of at least one second therapeutic agent useful for treating the cancer.
[0237] Embodiment 17. The method of Embodiment 16, wherein the cancer is breast cancer and the at least one second therapeutic agent is Soltamox® (tamoxifen), Arimidex® (anastrozole), Femara® (letrozole), Aromasin® (exemestane), Herceptin® (trastuzumab), Abraxane® (paclitaxel), Cytoxan® (cyclophosphamide), Taxol® (paclitaxel), Afinitor® (everolimus), Taxotere® (docetaxel), Xeloda® (capecitabine), Trexall® (methotrexate), Faslodex (fulvestrant), Adriamycin® (doxorubicin), Perjeta® (pertuzumab), Gemzar (gemcitabine), Tykerb® (lapatinib), Adrucil® (fluorouracil), Ibrance® (palbociclib), Verzenio® (abemaciclib), Fareston® (toremifene), Halaven® (eribulin), Menest, Kadcyla® (ado-trastuzumab emtransine), Androxy® (fluoxymesterone), Avastin® (bevacizumab), esterified estrogens, Herzuma® (trastuzumab), Ixempra® (ixabepilone), Kanjinti® (trastuzumab), Kisqali® (ribociclib), Ogivri® (trastuzumab), Ontruzant® (trastuzumab), Tepadina® (thiotepa), Trazimera® (trastuzumab), Velban® (vinblastine), Piqray® (alpelisib), Tecentriq® (atezolizumab), Enhertu® (fam-trastuzumab deruxtecan),
Herceptin, Hylecta™ (hyaluronidase/trastuzumab), Infugem® (gemcitabine), Kisqaii® Femara® Co-Pack (ribociclib and letrozole), Talzenna® (talazoparib), Trodelvy® (sacituzumab) or Tukysa™ (tukatinib).
[0238] Embodiment 18. The method of Embodiment 16, wherein the cancer is colon cancer and the at least one second therapeutic agent is Xeloda® (capeci tabine), El oxatin® (oxaliplatin), fluorouracil, A vastin® (bevacizumab), leucovorin, Camptosar® (irinotecan), Stivarga® (regorafenib), Erbitux® (cetuximab), Vectibix® (panitumumab), Lonsurf® (tipiracil/trifluridine), Zaltrap® (ziv-aflibercept), Betaseron® (interferon beta- lb), Fusilev® (levoleucovorin), Wellcocorin® (methotrexate), Keytruda® (pembrolizumab), Mvasi® (bevacizumab-awwb), Cyramza® (ramucirumab), Yervoy® (ipilmumab), Opdivo® (nivolumab), Braftovi® (encorafenib), Khapzory® (levoleucovorin) or Zirabev® (b evaci zumab -b vzr) .
[0239] Embodiment 19. The method of Embodiment 16, wherein the cancer is lung cancer and the at least one second therapeutic agent is Etopophos® (etoposide), Hycamtin® (topotecan), VePesid® (etoposide), Toposar® (etoposide), Opdivo® (nivolumab), Keytruda® (pembrolizumab), Tecentriq® (atezolizumab), Imfinizi® (durvalumab), methotrexate, cyclophosphamide, Carboplatin, Cisplatin, docetaxel, Gemcitabine, Irinotecan, Paclitaxel, Pemetrexed, Vinblastine, or Vinorelbine.
[0240] Embodiment 20. The method of Embodiment 16, wherein the cancer is pancreatic ductal cancer and the at least one second therapeutic agent is Gemzar® (Gemcitabine), fluorouracil, Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (irinotecan), bevacizumab, cetuximab, Infugem® (gemcitabine) or Lynparza® (olaparib).
[0241] Embodiment 21. The method of Embodiment 16, wherein the cancer is head and neck cancer and the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
[0242] Embodiment 22. The method of Embodiment 16, wherein the cancer is prostate cancer and the at least one second therapeutic agent is Suprefact® (buserelin), Firmagon® (degarelix), Zoladex® (goserelin), Vantas® (histrelin), Eligard® (leuprolide), Orgovyx® (relugolix), Trelstar® (triptorelin), Casodex® (bicalutamide), Eulexin®
(flutamide), Nilandron® (nilutamide), Zytiga® (biraterone acetate), Erleada® (apalutamide), or Xtandi® (enzalutamide).
[0243] Embodiment 23. The method of Embodiment 16, wherein the at least one second therapeutic agent is a STING agonist.
[0244] Embodiment 24. The method of any one of Embodiments 1-23, wherein the subject is (a) not infected with the HIV virus, (b) not suspected of being infected with the HIV virus, (c) not being treated for the HIV virus, and/or (d) not being treated to prevent the HIV virus.
[0245] Embodiment 25. A kit for carrying out the method of any one Embodiments 1-24, the kit comprising (i) a compound of Table 3; and (ii) and instructions for administering the compound of Table 3 to a subject having cancer.
[0246] Embodiment 26. The kit of Embodiment 25 further comprising at least one second therapeutic agent.
[0247] Embodiment 27. The method of any one of Embodiments 1-24, wherein the cells of the cancer are suspected to or exhibit deficiency of a DDR enzyme, e.g., one or more DDR enzymes of Table C, e.g., Pol η, Pol μ, and/or Pol θ, or the cells of the cancer are suspected to or exhibit amplification of a DDR gene, e.g., one or more DDR genes of Table C, e.g., POLE, POLM, and/or POLQ.
B. DNA damage repair enzyme inhibitors for use in treating cancer
[0248] Embodiment 1. A compound of Table 3 for use in treating cancer in a subj ect.
[0249] Embodiment 2. The compound of Table 3 for use of Embodiment 1, wherein the compound of Table 3 is 2-amino-9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-1 ,9-dihydro-6H-purin-6-one; 4-amino-1-
((2R,4 S, 5R)- 5 -ethynyl-4-hy dr oxy- 5 ~(hy droxymethy 1 )tetrahy drofuran-2-yl)-5 - fluoropyrimidin-2(1H)-one, or 4-amino-1-((2R,4S,5R)-5-ethynyl-4-hydroxy~5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(lH)-one.
[0250] Embodiment 3. The compound of Table 3 for use of Embodiment 1 , wherein the compound of Table 3 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-hydroxy- 2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile; 4-amino-1-((2R,4S,5R)-4-hydroxy~5- (hydroxymethyl)-5-methyltetrahydrofuran-2-yl)pyrimidin-2(1H)-one; or 4-amino-1- ((2R,4S,5R)-5-ethyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)- one.
[0251] Embodiment 4. The compound of Table 3 for use of Embodiment 1, wherein the compound of Table 3 is (2R,3S,5R)-5-(2,6-diamino-9H-purin-9-yl)-2-
(hydroxymethyl)-2-vinyltetrahydrofuran-3-oI; (2R,3S,5R)-5-(2,6-diamino-9H-purin-9- yl)-2-ethyl-2-(hydroxymethyl)tetrahydrofuran-3-ol; or 1-((2R,4S,5R)-5-ethynyl-4- hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione.
[0252] Embodiment 5. The compound of Table 3 for use of any one of Embodiments
1 -4, wherein the cancer is breast cancer, colon cancer, lung cancer, pancreatic ductal cancer, prostate cancer, ovarian cancer, or head and neck cancer.
[0253] Embodiment 6. The compound of Table 3 for use of Embodiment 5, wherein the cancer is breast cancer.
[0254] Embodiment 7. The compound of Table 3 for use of Embodiment 5, wherein the cancer is colon cancer.
[0255] Embodiment 8. The compound of Table 3 for use of Embodiment 5, wherein the cancer is lung cancer.
[0256] Embodiment 9. The compound of Table 3 for use of Embodiment 5, wherein the cancer is pancreatic ductal cancer.
[0257] Embodiment 10. The compound of Table 3 for use of Embodiment 5, wherein the cancer is prostate cancer.
[0258] Embodiment 11. The compound of Table 3 for use of Embodiment 5, wherein the prostate cancer is high-risk localized prostate cancer.
[0259] Embodiment 12. The compound of Table 3 for use of Embodiment 5, wherein the cancer is ovarian cancer.
[0260] Embodiment. 13. The compound of "fable 3 for use of Embodiment 5, wherein the cancer is head and neck cancer.
[0261] Embodiment 14. The compound of Table 3 for use of any one of Embodiments
1-5, wherein the subject has prostate cancer and the compound of Table 3 is administered as an adjuvant therapy.
[0262] Embodiment 15. The compound of Table 3 for use of any one of Embodiments
1 -5, wherein the subject has prostate cancer and the compound of Table 3 is administered as a neoadjuvant therapy.
[0263] Embodiment 16. The compound of Table 3 for use of any one of Embodiments
1-15 further comprising administering a therapeutically effective amount of at least one second therapeutic agent useful for treating the cancer.
[0264] Embodiment 17. The compound of Table 3 for use of Embodiment 16, wherein the cancer is breast cancer and the at least one second therapeutic agent is Soltamox® (tamoxifen), Arimidex® (anastrozole), Femara® (letrozole), Aromasin® (exemestane), Herceptin® (trastuzumab), Abraxane® (paclitaxel), Cytoxan® (cyclophosphamide), Taxol® (paclitaxel), Afinitor® (everolimus), Taxotere® (docetaxel), Xeloda® (capecitabine), Trexall® (methotrexate), Faslodex (fulvestrant), Adriamycin® (doxorubicin), Perjeta® (pertuzumab), Gemzar (gemcitabine), Tykerb® (lapatinib), Adrucil® (fluorouracil), Ibrance® (palbociclib), Verzenio® (abemaciclib), Fareston® (toremifene), Halaven® (eribulin), Menest, Kadcyla® (ado-trastuzumab emtransine), Androxy® (fluoxymesterone), Avastin® (bevacizumab), esterified estrogens, Herzuma® (trastuzumab), Ixempra® (ixabepilone), Kanjinti® (trastuzumab), Kisqali® (ribociclib), Ogivri® (trastuzumab), Ontruzant® (trastuzumab), Tepadina® (thiotepa), Trazimera® (trastuzumab), Velban® (vinblastine), Piqray® (alpelisib), Tecentriq® (atezolizumab), Enhertu® (fam-trastuzumab deaixtecan), Herceptin, Hylecta™ (hyaluronidase/trastuzumab), Infugem® (gemcitabine), Kisqali® Femara® Co-Pack (ribociclib and letrozole), Talzenna® (talazoparib), Trodelvy® (sacituzumab) or Tukysa™ (tukatinib).
[0265] Embodiment 18. The compound of Table 3 for use of Embodiment 16, wherein the cancer is colon cancer and the at least one second therapeutic agent is Xeloda® (capecitabine), Eloxatin® (oxaliplatin), fluorouracil, Avastin® (bevacizumab), leucovorin, Camptosar® (irinotecan), Stivarga® (regorafenib), Erbitux® (cetuximab), Vectibix® (panitumumab), Lonsurf® (tipiracil/trifluridine), Zaltrap® (ziv-aflibercept), Betaseron® (interferon beta-lb), Fusilev® (levoleucovorin), Wellcocorin® (methotrexate), Keytruda® (pembrolizumab), Mvasi® (bevacizumab-awwb), Cyramza® (ramucirumab), Yervoy® (ipilmumab), Opdivo® (nivolumab), Braftovi® (encorafenib), Khapzory® (levoleucovorin) or Zirabev® (bevacizurnab-bvzr).
[0266] Embodiment 19. The compound of Table 3 for use of Embodiment 16, wherein the cancer is lung cancer and the at least one second therapeutic agent is Etopophos® (etoposide), Hycamtin® (topotecan), VePesid® (etoposide), Toposar®
(etoposide), Opdivo® (nivolumab), Keytruda® (pembrolizumab), Tecentriq® (atezolizumab), Imfinizi® (durvaiumab), methotrexate, cyclophosphamide, Carboplatin, Cisplatin, docetaxel. Gemcitabine, Irinotecan, Paclitaxel, Pemetrexed, Vinblastine, or Vinorelbine.
[0267] Embodiment 20. The compound of Table 3 for use of Embodiment 16, wherein the cancer is pancreatic ductal cancer and the at least one second therapeutic agent is Gemzar® (Gemcitabine), fluorouracil, Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (irinotecan), bevacizumab, cetuximab, Infugem® (gemcitabine) or Lynparza® (olaparib).
[0268] Embodiment 21. The compound of Table 3 for use of Embodiment 16, wherein the cancer is head and neck cancer and the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
[0269] Embodiment 22. The compound of Table 3 for use of Embodiment 16, wherein the cancer is prostate cancer and the at least one second therapeutic agent is Suprefact® (buserelin), Firmagon® (degarelix), Zoladex® (goserelin), Vantas® (histrelin), Eligard® (leuprolide), Orgovyx® (relugolix), Trelstar® (triptorelin), Casodex® (bicalutamide), Eulexin® (flutamide), Nilandron® (nilutamide), Zytiga® (biraterone acetate), Erleada® (apalutamide), or Xtandi® (enzalutamide).
[0270] Embodiment 23. The compound of Table 3 for use of Embodiment 16, wherein the at least one second therapeutic agent is a STING agonist.
[0271] Embodiment 24. The compound of Table 3 for use of any one of Embodiments
1-23, wherein the subject is (a) not infected with the HIV virus, (b) not suspected of being infected with the HIV virus, (c) not being treated for the HIV virus, and/or (d) not being treated to prevent the HIV virus.
[0272] Embodiment 25. The compound of Table 3 for use of any one of Embodiments 1-24, wherein the cells of the cancer are suspected to or exhibit deficiency of a DDR enzyme, e.g., one or more DDR enzymes of Table C, e.g., Pol q, Pol μ, and/or Pol θ, or the cells of the cancer are suspected to or exhibit amplification of a DDR gene, e.g., one or more DDR genes of Table C, e.g., POLH, POLM, and/or POLQ.
C. DNA damage repair enzyme inhibitors in the manufacture of a medicament to treat cancer
[0273] Embodiment 1. Use of a compound of Table 3 in the manufacture of a medicament for treating cancer in a subject.
[0274] Embodiment 2. The use of Embodiment 1, wherein the compound of Table 3 is 2-amino-9-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)~ 1,9-dihydro-6H-purin-6-one; 4-amino-1-((2R,4S,5R)-5-ethynyl-4-hydroxy-5-
(hydroxymethyl)tetrahydrofuran-2-yI)-5-fluoropyrimidin-2(1H)-one; or 4-amino-1- ((2R,4S,5R)-5-ethynyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin” 2(1H)-one.
[0275] Embodiment 3. The use of Embodiment 1 , wherein the compound of T able 3 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-hydroxy-2-
(hydroxymethyl)tetrahydrofuran-2-carbonitrile; 4-amino-1-((2R,4S,5R)-4-hydroxy-5- (hydroxymethyl)-5-methyltetrahydrofuran~2-yl)pyrimidin-2(1H)-one; or 4-amino- 1 - ((2R,4S,5R)-5-ethyl-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)- one.
[0276] Embodiment 4. The use of Embodiment 1, wherein the compound of Table 3 is (2R,3S,5R)”5-(2,6-diamino-9H-purin-9-yl)”2-(hydroxymethyl)-2-vinyltetrahydrofuran- 3-ol; (2R,3S,5R)-5-(2,6-diamino-9H-purin-9-yl)-2-ethyl-2-
(hydroxymethyl)tetrahydrofuran-3-ol; or l-((2R,4S,5R)-5-ethynyl-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-5-fluoropyrimidine-2,4(lH,3H)-dione.
[0277] Embodiment 5. The use of any one of Embodiments 1-4, wherein the cancer is breast cancer, colon cancer, lung cancer, pancreatic ductal cancer, prostate cancer, ovarian cancer, or head and neck cancer.
[0278] Embodiment 6. The use of Embodiment 5, wherein the cancer is breast cancer.
[0279] Embodiment 7. The use of Embodiment 5, wherein the cancer is colon cancer.
[0280] Embodiment 8. The use of Embodiment 5, wherein the cancer is lung cancer.
[0281] Embodiment 9. The use of Embodiment 5, wherein the cancer is pancreatic ductal cancer.
[0282] Embodiment 10. The use of Embodiment 5, wherein the cancer is prostate cancer.
[0283] Embodiment 11. The use of Embodiment 5, wherein the prostate cancer is high-risk localized prostate cancer.
[0284] Embodiment 12. The use of Embodiment 5, wherein the cancer is ovarian cancer.
[0285] Embodiment 13. The use of Embodiment 5, wherein the cancer is head and neck cancer.
[0286] Embodiment 14. The use of any one of Embodiments 1-5, wherein the subject has prostate cancer and the compound of Table 3 is administered as an adjuvant therapy.
[0287] Embodiment 15. The use of any one of Embodiments 1-5, wherein the subject has prostate cancer and the compound of Table 3 is administered as a neoadjuvant therapy.
[0288] Embodiment 16. The use of any one of Embodiments 1-15 further comprising administering a therapeutically effective amount of at least one second therapeutic agent useful for treating the cancer.
[0289] Embodiment 17. The use of Embodiment 16, wherein the cancer is breast cancer and the at least one second therapeutic agent is Soltamox® (tamoxifen), Arimidex® (anastrozole), Femara® (letrozole), Aromasin® (exemestane), Herceptin® (trastuzumab), Abraxane® (paclitaxel), Cytoxan® (cyclophosphamide), Taxol® (paclitaxel), Afmitor® (everolimus), Taxotere® (docetaxel), Xeloda® (capecitabine), Trexall® (methotrexate), Faslodex (fulvestrant), Adriamycin® (doxorubicin), Perjeta® (pertuzumab), Gemzar (gemcitabine), Tykerb® (lapatinib), Adrucil® (fluorouracil), Ibrance® (palbociclib), Verzenio® (abemaciclib), Fareston® (toremifene), Halaven® (eribulin), Menest, Kadcyla® (ado-trastuzumab emtransine), Androxy® (fluoxymesterone), Avastin® (bevacizumab), esterified estrogens, Herzuma® (trastuzumab), Ixempra® (ixabepilone), Kanjinti® (trastuzumab), Kisqali® (ribociclib), Ogivri® (trastuzumab), Ontruzant® (trastuzumab), Tepadina® (thiotepa), Trazimera® (trastuzumab), Velban® (vinblastine), Piqray® (alpelisib), Tecentriq® (atezolizumab), Enhertu® (fam-trastuzumab deruxtecan), Herceptin, Hylecta™ (hyaluronidase/trastuzumab), Infugem® (gemcitabine), Kisqali® Femara® Co-Pack (ribociclib and letrozole), Talzenna® (talazoparib), Trodelvy® (sacituzumab) or Tukysa™ (tukatinib).
[0290] Embodiment 18. The use of Embodiment 16, wherein the cancer is colon cancer and the at least one second therapeutic agent is Xeloda® (capecitabine), Eloxatin® (oxaliplatin), fluorouracil, Avastin® (bevacizumab), leucovorin, Camptosar® (irinotecan), Stivarga® (regorafenib), Erbitux® (cetuximab), Vectibix® (panitumumab), Lonsurf® (tipi racil/trifluri dine), Zaltrap® (ziv-aflibercept), Betaseron® (interferon beta-lb), Fusilev® (levoleucovorin), Wellcocorin® (methotrexate), Keytruda® (pembrolizumab), Mvasi® (bevacizumab-awwb), Cyramza® (ramucirumab), Yervoy® (ipilmumab), Opdivo® (nivolumab), Braftovi® (encorafenib), Khapzory® (levoleucovorin) or Zirabev® (bevacizumab-bvzr).
[0291] Embodiment 19. The use of Embodiment 16, wherein the cancer is lung cancer and the at least one second therapeutic agent is Etopophos® (etoposide), Hycamtin® (topotecan), VePesid® (etoposide), Toposar® (etoposide), Opdivo® (nivolumab), Keytruda® (pembrolizumab), Tecentriq® (atezolizumab), Imfmizi® (durvalumab), methotrexate, cyclophosphamide, Carboplatin, Cisplatin, docetaxel, Gemcitabine, Irinotecan, Paclitaxel, Pemetrexed, Vinblastine, or Vinorelbine.
[0292] Embodiment 20. The use of Embodiment 16, wherein the cancer is pancreatic ductal cancer and the at least one second therapeutic agent is Gemzar® (Gemcitabine), fluorouracil, Afinitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (irinotecan), bevacizumab, cetuximab, Infugem® (gemcitabine) or Lynparza® (olaparib).
[0293] Embodiment 21. The use of Embodiment 16, wherein the cancer is head and neck cancer and the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
[0294] Embodiment 22. The use of Embodiment 16, wherein the cancer is prostate cancer and the at least, one second therapeutic agent is Suprefact® (buserelin), Firmagon® (degarelix), Zoladex® (goserelin), Vantas® (histrelin), Eligard® (leuprolide), Orgovyx® (relugolix), Trelstar® (triptorelin), Casodex® (bicalutamide), Eulexin® (flutamide), Nilandron® (nilutamide), Zytiga® (biraterone acetate), Erleada® (apalutamide), or Xtandi® (enzalutamide).
[0295] Embodiment 23. The use of Embodiment 16, wherein the at least one second therapeutic agent is a STING agonist.
[0296] Embodiment 24. The use of any one of Embodiments 1-23, wherein the subject is (a) not infected with the HIV virus, (b) not suspected of being infected with the HIV virus, (c) not being treated for the HIV virus, and/or (d) not being treated to prevent the HIV virus.
[0297] Embodiment 25. The use of any one of Embodiments 1-24, wherein the cells of the cancer are suspected to or exhibit deficiency of a DDR enzyme, e.g., one or more DDR enzymes of Table C, e.g., Pol η, Pol μ, and/or Pol θ, or the cells of the cancer are suspected to or exhibit amplification of a DDR gene, e.g., one or more DDR genes of Table
C, e.g., POLII, POLM, and/or POLQ.
D. Reverse transcriptase inhibitors for treating cancer.
[0298] Embodiment 1. A method of treating cancer in a patient, wherein the cells of the cancer are suspected to or exhibit deficiency of a DNA repair enzyme, comprising administering to the patient an effective amount of a reverse transcriptase inhibitor (RTI) that is also a Pol θ inhibitor, with the proviso that, the RTI is not ddC.
[0299] Embodiment 2. The method of Embodiment 1, further comprising administering at least one second agent that is useful for the treatment of cancer.
[0300] Embodiment 3. The method of Embodiment 2, wherein the at least one second agent that is useful for the treatment of cancer is a poly ADP ribose polymerase
(PARP) inhibitor, an ATM inhibitor, a weel inhibitor, or an ATR inhibitor.
[0301] Embodiment 4. The method of Embodiment 1, wherein the cells are resistant to PARP inhibition.
[0302] Embodiment 5. The method of Embodiment 2, wherein the second agent is a
PARP inhibitor.
[0303] Embodiment 6. The method of Embodiment 5, wherein the P AR P inhibitor is olaparib, rucaparib, niraparib or talazoparib.
[0304] Embodiment 7. The method of any one of Embodiments 1-6, wherein the DNA repair enzyme is encoded by at least one homologous recombination (HR) gene.
[0305] Embodiment 8. The method of Embodiment 7, wherein the at least one HR gene is ATM, ATR, BRCA1, BRCA2, BARD1, RAD51C, RAD50, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL,
FANCM, PALB2 (FANCN), FANCP (BTBD12), ERCC4 (FANCQ), FPEN, CDK12, MRE11, NBS1, NBN, CLASPIN, BLM, WRN, SMARCA2, SMARCA4 LIG1, RPA1, BRI P l or PTEN.
[0306] Embodiment 9. The method of any one of Embodiments 1-8, wherein the RTI is lamivudine (3TC), zidovudine (AZT), tenofovir, tenofovir disoproxil, tenofovir alafenamide, stavudine (d4T), didanosine (ddl), emtricitabine (FTC), entecavir (ETV), 2',3'-dideoxyguanosine (ddG), 2’, 3 '-dideoxyadenosine (ddA), 2'-fluoro-2',3'- dideoxyarabinosyladenine (F-ddA), efavirenz (EFV), nevirapine (NVP), or abacavir (ABC), adefovir dipivoxil, telbivudine, or islatravir.
[0307] Embodiment 10. The method of any one of Embodiments 1-8, wherein the RTI is any one or more of the compounds of Table A, or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof.
[0308] Embodiment 11. The method of any one of Embodiments 1-8, wherein the RTI is any one or more of the compounds of Table B, or a pharmaceutically acceptable salt or solvate thereof, or a tautomer thereof.
[0309] Embodiment 12. The method of Embodiments 1-11, wherein the cancer is breast cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and/or BRCA2 genes.
[0310] Embodiment 13. The method of Embodiments 1-11, wherein the cancer is prostate cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and or BRCA2 genes.
[0311] Embodiment 14. The method of Embodiments 1-11, wherein the cancer is ovarian cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and /or BRCA2 genes.
[0312] Embodiment 15. The method of Embodiments 1-11, wherein the cancer is pancreatic cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and/or BRCA2 genes.
[0313] Embodiment 16. The method of any one of Embodiments 1-15, wherein the cells of the cancer exhibit overexpression of PolQ compared to the corresponding cells that are not cancer cells.
[0314] Embodiment 17. The method of any one of Embodiments 1-16, wherein the RTI inhibits human LINE- 1 retrotransposition with a half maximal inhibitory’ concentration of less than 100 nM in a HeLa cell-based dual-luciferase assay.
[0315] Embodiment 18. The method of any one of Embodiments 1-16, wherein the RTI inhibits human LINE-1 retrotransposition with a half maximal inhibitory concentration of less than 50 nM in a HeLa cell-based dual-luciferase assay.
[0316] Embodiment 19. The method of any one of Embodiments 1-16, wherein the RTI inhibits human LINE-1 retrotransposition with a half maximal inhibitory concentration of less than 10 nM in a HeLa cell-based dual-luciferase assay.
[0317] Embodiment 20. The method of Embodiment 2 for the treatment of breast cancer, wherein the at least one second therapeutic agent is Soltamox® (tamoxifen), Arimidex® (anastrozole), Femara® (letrozole), Aromasin® (exemestane), Herceptin® (trastuzumab), Abraxane® (paclitaxel), Cytoxan® (cyclophosphamide), Taxol® (paclitaxel), Afinitor® (everolimus), Taxotere® (docetaxel), Xeloda® (capecitabine), Trexall® (methotrexate), Faslodex (fulvestrant), Adriamycin® (doxorubicin), Perjeta® (pertuzumab), Gemzar (gemcitabine), Tykerb® (lapatinib), Adrucil® (fluorouracil), Ibrance® (palbociclib), Verzenio® (abemaciclib), Fareston® (toremifene), Halaven® (eribulin), Menest, Kadcyla® (ado-trastuzumab emtransine), Androxy® (fluoxymesterone), Avastin® (bevacizumab), esterified estrogens, Herzuma® (trastuzumab), Ixempra® (ixabepilone), Kanjinti® (trastuzumab), Kisqali® (ribociclib), Ogivri® (trastuzumab), Ontruzant® (trastuzumab), Tepadina® (thiotepa), Trazimera® (trastuzumab), Velban® (vinblastine), Piqray® (alpelisib), Tecentriq® (atezolizumab), Enhertu® (fam-trastuzumab deruxtecan), Herceptin, Hylecta™ (hyaiuronidase/trastuzumab), Infugem® (gemcitabine), Kisqali® Femara® Co-Pack (ribociclib and letrozole), Talzenna® (talazoparib), Trodelvy® (sacituzumab) or Tukysa™ (tukatinib).
[0318] Embodiment 21 . The method of Embodiment 2 for the treatment of colon cancer, wherein the at least one second therapeutic agent is Xeloda® (capecitabine), El oxatin® (oxaliplatin), fluorouracil, Avastin® (bevacizumab), leucovorin, Camptosar® (irinotecan), Stivarga® (regorafenib), Erbitux® (cetuximab), Vectibix® (panitumumab), Lonsurf® (tipiracil/trifluridine), Zaltrap® (ziv-aflibercept), Betaseron® (interferon betalb), Fusilev® (levoleucovorin), Wellcocorin® (methotrexate), Keytruda®
(pembrolizumab), Mvasi® (bevacizumab-awwb), Cyramza® (ramucirumab), Yervoy® (ipilmumab), Opdivo® (nivolumab), Braftovi® (encorafenib), Khapzory® (levoleucovorin) or Zirabev® (bevacizumab-bvzr).
[0319] Embodiment 22. The method of Embodiment 2 for the treatment of lung cancer, wherein the at least one second therapeutic agent is Etopophos® (etoposide), Hycamtin® (topotecan), VePesid® (etoposide), Toposar® (etoposide), Opdivo® (nivolumab), Keytruda® (pembrolizumab), Tecentriq® (atezolizumab), Itnfinizi® (durvalumab), methotrexate, cyclophosphamide, Carboplatin, Cisplatin, docetaxel, Gemcitabine, Irinotecan, Paclitaxel, Pemetrexed, Vinblastine, or Vinorelbine.
[0320] Embodiment 23. The method of Embodiment 2 for the treatment of pancreatic ductal cancer, wherein the at least one second therapeutic agent is Gemzar® (Gemcitabine), fluorouracil, Afmitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (irinotecan), bevacizumab, cetuximab, Infugem® (gemcitabine) or Lynparza® (olaparib).
[0321] Embodiment 24. The method of Embodiment 2 for the treatment of head and neck cancer, wherein the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
[0322] Embodiment 25. The method of Embodiment 2 for the treatment of prostate cancer, wherein the at least one second therapeutic agent is Supr efact® (buserelin), Firmagon® (degarelix), Zoladex® (goserelin), Vantas® (histrelin), Eligard® (leuprolide), Orgovyx® (relugolix), Trelstar® (triptorelin), Casodex® (bicalutamide), Eulexin® (flutamide), Nilandron® (nilutamide), Zytiga® (abiraterone acetate), Erleada® (apalutamide), or Xtandi® (enzalutamide).
[0323] Embodiment 26. The method of Embodiment 2, wherein the at least one second therapeutic agent is a STING agonist.
[0324] Embodiment 27. The method of any one of Embodiments 1-26, wherein the patient is (a) not infected with the HIV virus, (b) not suspected of being infected with the HIV virus, (c) not being treated for the HIV virus, and/or (d) not being treated to prevent the HIV virus.
[0325] Embodiment 28. The method of any one of Embodiments 1-27 wherein the
RTI is a nucleoside reverse transcriptase inhibitor (NRTI).
[0326] Embodiment 29. A kit for carrying out the method of any one Embodiments
1-28, the kit comprising (i) a RTI; and (ii) and instructions for administering the RTI to a patient having cancer.
[0327] Embodiment 30. The kit of Embodiment 29, wherein the kit contains instructions for admini stering the RTI according to an intermittent dosing schedule.
[0328] Embodiment 31. The kit of Embodiment 29 or 30 further comprising at least one second therapeutic agent for the treatment of cancer.
[0329] Embodiment 32. The kit of Embodiment 29 or 30, further comprising instructions for administering the NRTI together with at least one second therapeutic agent for the treatment of cancer.
EXAMPLES
EXAMPLE 1
Cancer Cell Proliferation Activity
[0330] Dose response relationships on cell proliferation was assessed for representative compounds on cancer cell lines. See Table 3. Briefly, compound treatment of cells started one day after seeding with a final DMSO concentration of 0.1%, and was performed by nanodrop-dispensing using a Tecan Dispenser. 0.1% DMSO (solvent) and Staurosporine (10 gM) served as high control (100% viability) and low control (0% viability), respectively. Cells were cultured in the appropriate media. For the assays, cells were seeded in white cell culture-treated flat and clear bottom multiwell plates and incubated at 37 °C overnight before compound was added. After incubation for 72 h at 37°C at 5% or 10% CO2 dependent on the medium, cell plates were equilibrated to room temperature for one hour, CellTiterGlo reagent (Promega) was added and luminescence was measured approximately an hour later using a luminometer.
[0331] Raw data were converted into percent cell viability relative to the high and low- control, which were set to 100% and 0%, respectively. IC50 calculation was performed using GraphPad Prism software with a variable slope sigmoidal response fitting model using 0% viability as bottom constraint and 100% viability as top constraint.
EXAMPLE 2
Synthesis of 4-amino-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)-5-methyltetrahydrofuran-2- yl)pyrimidin-2(1H)-one (Cpd. No. 5)
(benzyloxy)-5-((benzyloxy)methyl)-5-methyltetrahydrofuran-3-yl) O-phenyl carbonothioate. To a stirring suspension of N-(l-((2R,3R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3- hydroxy-5-methyltetrahydrofuran-2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)benzamide (2.00 g, 3.69 mmol) in anhydrous acetonitrile (74.4 mL) were added successively DMAP (1 .36 g, 11 .1 mmol) and O-phenyl chlorothionoformate (776 pL, 5.54 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for ca. 1 h, then the mixture was concentrated in vacuo to remove the volatiles. The residue was taken up in EtOAc and the solution washed successively with 5% aqueous citric acid solution and water. The organics were dried (anhyd. Na2SO4), filtered and concentrated in vacuo to furnish the crude product. Purification by flash chromatography on SiO2 (eluent: 5% IPA in DCM) afforded the title compound (2.38 g, 3.50 mmol, 95%) as a cream solid. LC-MS (ESI) ni/z 679.6 [M+2H]+. LC- MS RT === 1 .76 min; Method H.
[0334] Step 2: N-(l-((2R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-5- methyltetrahydroforan-2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)benzamide. To a stirring suspension of O-((2R,3R,4S,5R)-2-(4-benzamido-2-oxopyrimidin-l(2H)-yl)-4-(benzyloxy)-5- ((benzyloxy)methyl)-5-methyltetrahydrofuran-3-yl) (7-phenyl carbonothioate (2.35 g, 3.47 mmol) in anhydrous toluene (23.5 mL) were added AIBN (285 nig, 1.73 mmol) and tris(trimethylsilyl)silane (2.21 mL, 6,93 mmol) at ambient temperature with stirring. The resulting mixture was heated to 85 °C with stirring for ca. 1 h before cooling to ambient temperature. The reaction mixture was then diluted with EtOAc (40 mL) and washed with 0.5M
aqueous KF solution (3 x 20 mL). The organics were then washed with saturated aqueous NaCl solution, dried (anhyd. Na2SO4), filtered and concentrated in vacuo to afford the crude product. Purification by flash chromatography on SiO2 (eluent: 30% EtOAc in DCM) afforded the title compound (895 mg, 1.71 mmol, 49%) as a white solid. LC-MS (ESI) m/z 526.5 [M+H]+. LC- MS RT - 1 ,54 min; Method H
[0335] Step 3: 4-amino-1-((2R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-5- methyltetrahydrofuran-2-yl)pyrimidin-2(1H)-one. DBU (107 pL, 705 pmol) was added to a solution of N-(1-((2R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-5-methyltetrahydrofuran- 2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)benzamide (247 mg, 470 pmol) in MeOH (4.94 mL), and the mixture was stirred at ambient temperature for ca. 30 mins. The reaction mixture was then adsorbed onto silica gel and purified by flash chromatography on SiO2 (eluent: 15% MeOH in DCM) to provide the title compound (191 mg, 453 pmol, 96%). LC-MS (ESI) m/z 422.5 [M+H] + . LC-MS RT = 1 .20 min; Method H.
[0336] Step 4: 4-amino-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)-5- methyltetrahydrofuran-2-yl)pyrimidin-2(1H)-one (Cpd. No. 5). A flame-dried round-bottomed flask equipped with a magnetic stirrer bar was charged with a solution of 4-amino-1- ((2R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-5-methyltetrahydrofuran-2-yl)pyrimidin- 2(1H)-one (186 mg, 441 pmol) in MeOH (17.7 mL) under nitrogen atmosphere. Palladium(II) chloride (78.3 mg, 441 pmol) was added in one portion, then the reaction mixture was sparged with hydrogen gas from a balloon for ca. 30 seconds. The reaction mixture was then allowed to stir under hydrogen (1 atm) for ca. 1 h. The hydrogen balloon was then removed, and the vessel purged under positive pressure of nitrogen for ca. 30 seconds. Triethylamine (ca. 1 mL) was added dropwise to quench HC1 by-products, then the reaction mixture was filtered through a short pad of Celite®, rinsing with small portions of MeOH, and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on SiO2 (eluent: 30% MeOH in DCM) to furnish Cpd. No. 5 (90 mg, 375 pmol, 85%) as a white amorphous solid after lyophilization. 41 NMR (400 MHz, DMSO-d6) δ 7.88 (d, J == 7,4 Hz, 1H), 7.11 (br. S, 1H), 7.04 (br. S, 1H), 6.06 (t, ./= 6.4 Hz, 1H), 5.68 (d, J= 7.4 Hz, 1H), 5.09 (d, J= 4.8 Hz, 1H), 5.05 (t, J == 5,4 Hz, 1H), 4.16 (di, ./ 6.3, 4,8 Hz, 1H), 3.41 (dd, J == 11.5, 5.5 Hz, 1H), 3.36 (dd, J == 11.5, 5.5 Hz, 1H), 2. 18 (ddd, J == 13.2, 6.3, 4.8 Hz, 1H), 2.03 (dt, ./ 13.1 , 6.4 Hz, 1H), 1.05 (s, 3H). LC-MS (ESI) m/z 240.3 [M-H]". LC-MS RT = 0.20 min; Method A.
Tabb 4A
[0337] All patents, patent application, and publications cited herein are fully incorporated by reference herein.
[0338] It is to be appreciated that the Detailed Description section, and not the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections may set forth one or more but not all exemplary embodiments of the present invention as contemplated by the inventor(s), and thus, are not intended to limit the present invention and the appended claims in any way.
[0339] The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying knowledge within the skill of the art, readily modify and/or adapt for various applications such specific embodiments, without undue experimentation, without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It i s to be understood that, the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.
[0340] The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.
Claims
1. A method of treating cancer in a patient, wherein the cells of the cancer are suspected to or exhibit deficiency of a DNA damage repair (DDR) enzyme, comprising administering to the patient an effective amount of a compound that is:
2. The method of claim I, wherein the cancer is adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS- related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma.
angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy/ cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B- cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary' effusion lymphoma, preimary peritoneal
cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter’s transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, sornatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin’s tumor, or Wilms' tumor.
3. The method of claim 1, wherein the cancer is breast cancer, colon cancer, lung cancer, pancreatic ductal cancer, prostate cancer, ovarian cancer, or head and neck cancer.
4. The method of any one of claims 1-3, further comprising administering at least one second agent that is useful for the treatment of cancer.
5. The method of claim 4, wherein the at least one second agent that is useful for the treatment of cancer is a poly ADP ribose polymerase (PARP) inhibitor, an ATM inhibitor, a wee i inhibitor, or an ATR inhibitor.
6. The method of any one of claims 1-3, wherein the cells are resistant to PARP inhibition.
7. The method of claim 4, wherein the second agent is a PARP inhibitor.
8. The method of claim 7, wherein the PARP inhibitor is olaparib, rucaparib, niraparib or talazoparib.
9. The method of any one of claims 1-8, wherein the DNA repair enzyme is encoded by at least one homologous recombination (HR) gene that is A TM, A TR, BRCA 1, BRCA2, BARE)],
RAD51C, RAD50, CHEKI, CHEK.2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 (FANCN), FANCP (BTBD12), ERCC4 (FANCQ), FPEN, CDK12, MREll, NBSI, NBN, CLASPIN, BLM, WRN SMARCA2, SMAR.CA4 LIGI , RPA1, BRIPI or PTEN.
10. The method of claims 1-9, wherein the cancer is breast cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA 1 and/or BRCA2 genes.
11. The method of claims 1 -9, wherein the cancer is prostate cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and or BRCA2 genes.
12. The method of claims 1-9, wherein the cancer is ovarian cancer, and the cells of the cancer exhibit deficiency or loss of function of BRCA1 and /or BRCA2 genes.
13. The method of claims 1-9, wherein the cancer is pancreatic cancer, and the cells of the cancer exhibi t deficiency or loss of function of BRCA 1 and/or BRCA2 genes.
14. The method of any one of claims 1-13, wherein the cells of the cancer exhibit overexpression of PolQ compared to the corresponding cells that are not cancer cells.
15. The method of claim 4 for the treatment of breast cancer, wherein the at least one second therapeutic agent is Soltamox® (tamoxifen), Arimidex® (anastrozole), Femara® (letrozole), Aromasin® (exemestane), Herceptin® (trastuzumab), Abraxane® (paclitaxel), Cytoxan® (cyclophosphamide), Taxol® (paclitaxel), Afmitor® (everolimus), Taxotere® (docetaxel), Xeloda® (capeci tabine), Trexall® (methotrexate), Faslodex (fulvestrant), Adriamycin® (doxorubicin), Pen eta® (pertuzumab), Gemzar (gemcitabine), Tykerb® (lapatinib), Adrucil® (fluorouracil), Ibrance® (palbociclib), Verzenio® (abemaciclib), Fareston® (toremifene), Halaven® (eribulin), Menest, Kadcyla® (ado-trastuzumab emtransine), Androxy® (fluoxymesterone), Avastin® (bevacizumab), esterified estrogens, Herzuma® (trastuzumab), Ixempra® (ixabepilone), Kanjinti® (trastuzumab), Kisqali® (ribociclib), Ogivri® (trastuzumab), Ontruzant® (trastuzumab), Tepadina® (thiotepa), Trazimera® (trastuzumab), Velban® (vinblastine), Piqray® (alpelisib), Tecentriq® (atezolizumab), Enhertu® (fam-trastuzumab
deruxtecan), Herceptin, Hylecta™ (hyaluronidase/trastuzumab), Infugem® (gemcitabine), Kisqali® Femara® Co-Pack (ribociclib and letrozole), Talzenna® (talazoparib), Trodelvy® (sacituzumab) or Tukysa™ (tukatinib).
16. The method of claim 4 for the treatment of colon cancer, wherein the at least one second therapeutic agent is Xeloda® (capecitabine), Eloxatin® (oxaliplatin), fluorouracil, Avastin® (bevacizumab), leucovorin, Camptosar® (irinotecan), Stivarga® (regorafenib), Erbitux® (cetuximab), Vectibix® (panitumumab), Lonsurf® (tipiracil/trifluridine), Zaltrap® (ziv- aflibercept), Betaseron® (interferon beta- lb), Fusilev® (levoleucovorin), Wellcocorin® (methotrexate), Keytruda® (pembrolizumab), Mvasi® (bevacizumab-awwb), Cyramza® (ramucirumab), Yervoy® (ipilmumab), Opdivo® (nivolumab), Braftovi® (encorafenib), Khapzory® (levoleucovorin) or Zirabev® (bevacizumab-bvzr).
17. The method of claim 4 for the treatment of lung cancer, wherein the at least one second therapeutic agent is Etopophos® (etoposide), Hycamtin® (topotecan), VePesid® (etoposide), Toposar® (etoposide), Opdivo® (nivolumab), Keytruda® (pembrolizumab), Tecentriq® (atezolizumab), Imfinizi® (durvalumab), methotrexate, cyclophosphamide, Carboplatin, Cisplatin, docetaxel, Gemcitabine, Irinotecan, Paclitaxel, Pemetrexed, Vinblastine, or Vinorelbine.
18. The method of claim 4 for the treatment of pancreatic ductal cancer, wherein the at least one second therapeutic agent is Gemzar® (Gemcitabine), fluorouracil, Afmitor® (everolimus), Tarceva® (erlotinib), Abraxane® (paclitaxel), capecitabine, Sutent® (sunitinib), pancreatin, methotrexate, Zanosar® (streptozocin), Mutamycin® (mitomycin), Onivyde® (irinotecan), bevacizumab, cetuximab, Infugem® (gemcitabine) or Lynparza® (olaparib).
19. The method of claim 4 for the treatment of head and neck cancer, wherein the at least one second therapeutic agent is Erbituz® (cetuximab), Taxotere® (docetaxel), Trexall® (methotrexate), Keytruda® (pembrolizumab) or Opdivo® (nivolumab).
20. The method of claim 4 for the treatment of prostate cancer, wherein the at least one second therapeutic agent is Suprefact® (buserelin), Firmagon® (degarelix), Zoladex® (goserelin).
Vantas® (histrelin), Eligard® (leuprolide), Orgovyx® (relugolix), Trelstar® (triptorelin), Casodex® (bicalutamide), Eulexin® (flutamide), Nilandron® (nilutamide), Zytiga® (abiraterone acetate), Erleada® (apalutamide), or Xtandi® (enzalutamide).
21. The method of claim 4, wherein the at least one second therapeutic agent is a STING agonist.
22. The method of any one of claims 1-21, wherein the patient is (a) not infected with the HIV virus, (b) not suspected of being infected with the HIV virus, (c) not being treated for the HIV virus, and/or (d) not being treated to prevent the HIV virus.
23. A kit for carrying out the method of any one claims 1 -22, the kit comprising (i) the compound; and (ii) and instructions for administering the compound to a patient having cancer.
24. The kit of claim 23 further comprising at least one second therapeutic agent for the treatment of cancer,
25. The kit of claim 29 or 30, further comprising instructions for administering the compound together with at least one second therapeutic agent for the treatment of cancer.
26. A method, comprising administering a therapeutically effective amount of a compound of Table 3 to a subject in need thereof, wherein:
(a) the subject has cancer; and
(b) the cancer is characterized as having an overexpression of one or more DNA damage repair enzymes.
27. A method of treating a subject having cancer, the method comprising:
(a) determining whether an overexpression of one or more DNA damage repair enzymes is present or absent in a biological sample taken from the subject; and
(b) administering a therapeutically effective amount a compound of Table 3 to the subject if an overexpression of one or more DNA damage repair enzymes is present in the biological sample.
28. A method of identifying whether a subject having cancer as a candidate for treatment with a compound of Table 3, the method comprising:
(a) determining whether an overexpression of one or more DNA damage repair enzymes is present or absent in a biological sample taken from the subject; and
(b) identifying the subject as being a candidate for treatment if an overexpression of one or more DNA damage repair enzymes is present; or
(c) identifying the subject as not being a candidate for treatment if over express! on of one or more DNA damage repair enzymes is absent.
29. A method of predicting treatment outcome in a subject having cancer, the method comprising determining whether an overexpression of one or more DNA damage repair enzymes is present or absent in a biological sample taken from the subject, wherein:
(a) the presence of an overexpression of one or more DNA damage repair enzymes in the biological sample indicates that administering a compound of Table 3 to the subject will likely cause a favorable therapeutic response; and
(b) the absence of an overexpression of one or more DNA damage repair enzymes in the biological sample indicates that administering a compound of Table 3 to the subject will likely cause an unfavorable therapeutic response.
30. The method of any one of claims 26-29, wherein the one or more DNA damage repair enzymes comprise Pol θ, Pol μ, and/or Pol μ.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202263325482P | 2022-03-30 | 2022-03-30 | |
US63/325,482 | 2022-03-30 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2023192505A2 true WO2023192505A2 (en) | 2023-10-05 |
WO2023192505A3 WO2023192505A3 (en) | 2023-11-09 |
Family
ID=88203288
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2023/016940 WO2023192505A2 (en) | 2022-03-30 | 2023-03-30 | Method for treating cancer with a dna damage repair enzyme inhibitor |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2023192505A2 (en) |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002076280A2 (en) * | 2001-03-23 | 2002-10-03 | Yeda Research And Development Co. Ltd. | Methods and kits for determing a risk to develop cancer, for evaluating an effectiveness and dosage of cancer therapy and for correlating between an activity of a dna repair enzyme and a cancer |
JP6603133B2 (en) * | 2013-02-06 | 2019-11-06 | ブランダイス ユニバーシティー | Treatment of DNA damage and mitochondrial dysfunction using palm fruit |
CN106999734B (en) * | 2014-09-29 | 2020-06-16 | 得克萨斯大学体系董事会 | Prediction of response to PARP inhibitors and combination therapies targeting C-MET and PARP1 |
AU2019326768A1 (en) * | 2018-08-24 | 2021-03-18 | Agricultural University Of Athens (Aua) | 2,6-bis(((1H-benzo[d]imidazol-2-yl)thio)methyl)pyridine and N2,N6-dibenzylpyridine-2,6-dicarboxamide derivatives and related compounds as phosphoinositide 3-kinase (PI3K) inhibitors for treating cancer |
IL301560A (en) * | 2020-09-23 | 2023-05-01 | Primefour Therapeutics Inc | Method for treating cancer with a reverse transcriptase inhibitor |
-
2023
- 2023-03-30 WO PCT/US2023/016940 patent/WO2023192505A2/en unknown
Also Published As
Publication number | Publication date |
---|---|
WO2023192505A3 (en) | 2023-11-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6660993B2 (en) | Deoxyuridine triphosphatase inhibitor | |
EP3110818B1 (en) | 9h-pyrimido[4,5-b]indoles and related analogs as bet bromodomain inhibitors | |
JP2023153949A (en) | Inhibitors of human ezh2, and methods of use thereof | |
US11046703B2 (en) | Small molecule MDM2 protein degraders | |
WO2019090263A1 (en) | Diagnostic and therapeutic methods for cancer | |
US20230293526A1 (en) | Method for treating cancer with a reverse transcriptase inhibitor | |
US20130131139A1 (en) | Ror1 as a gene target in acute lymphoblastic leukemia | |
JP2024038485A (en) | PIM kinase inhibitors for the treatment of myeloproliferative neoplasms and cancer-associated fibrosis | |
WO2017003845A1 (en) | Biomarkers of response to selective inhibitors of aurora a kinase | |
TW202228723A (en) | Line-1 inhibitors to treat disease | |
TWI595879B (en) | Prediction of therapeutic effect in patients with colorectal cancer with TK1 protein hyperactivity | |
WO2016148969A1 (en) | Kub5/hera as a determinant of sensitivity to dna damage | |
WO2023192505A2 (en) | Method for treating cancer with a dna damage repair enzyme inhibitor | |
US20180346988A1 (en) | Znf532 for diagnosis and treatment of cancer | |
US10202357B2 (en) | Class of quinolone heterocyclic aromatic molecules for cancer treatment | |
WO2023192499A1 (en) | Nucleosides for treating cancer | |
US20230158034A1 (en) | Co-treatment with cdk4/6 and cdk2 inhibitors to suppress tumor adaptation to cdk2 inhibitors | |
US20190169134A1 (en) | Novel class of quinolone heterocyclic aromatic molecules for cancer treatment | |
US20220128562A1 (en) | Biomarkers predictive of cancer cell response to ml329 or a derivative thereof | |
WO2024054898A1 (en) | Onvansertib and parp inhibitor combination | |
CN118043053A (en) | Methods of treating cancer | |
Agulló‑Ortuño et al. | CDK Signaling |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23781823 Country of ref document: EP Kind code of ref document: A2 |