JP7034085B2 - Aml及びmdsの治療のためのraraアゴニスト - Google Patents
Aml及びmdsの治療のためのraraアゴニスト Download PDFInfo
- Publication number
- JP7034085B2 JP7034085B2 JP2018553078A JP2018553078A JP7034085B2 JP 7034085 B2 JP7034085 B2 JP 7034085B2 JP 2018553078 A JP2018553078 A JP 2018553078A JP 2018553078 A JP2018553078 A JP 2018553078A JP 7034085 B2 JP7034085 B2 JP 7034085B2
- Authority
- JP
- Japan
- Prior art keywords
- inhibitor
- irf8
- rara
- gene
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 208000031261 Acute myeloid leukaemia Diseases 0.000 title claims description 153
- 238000011282 treatment Methods 0.000 title claims description 58
- 239000000556 agonist Substances 0.000 title description 108
- 108020004999 messenger RNA Proteins 0.000 claims description 263
- 239000003623 enhancer Substances 0.000 claims description 238
- 210000004027 cell Anatomy 0.000 claims description 212
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 137
- MUTNCGKQJGXKEM-UHFFFAOYSA-N tamibarotene Chemical compound C=1C=C2C(C)(C)CCC(C)(C)C2=CC=1NC(=O)C1=CC=C(C(O)=O)C=C1 MUTNCGKQJGXKEM-UHFFFAOYSA-N 0.000 claims description 137
- 229950010130 tamibarotene Drugs 0.000 claims description 137
- 206010028980 Neoplasm Diseases 0.000 claims description 121
- 239000003112 inhibitor Substances 0.000 claims description 106
- 201000011510 cancer Diseases 0.000 claims description 98
- 239000000203 mixture Substances 0.000 claims description 88
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 claims description 69
- 239000000090 biomarker Substances 0.000 claims description 62
- 239000000523 sample Substances 0.000 claims description 62
- 101150037497 Irf8 gene Proteins 0.000 claims description 58
- 239000003814 drug Substances 0.000 claims description 51
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 41
- 239000012472 biological sample Substances 0.000 claims description 39
- 229940124597 therapeutic agent Drugs 0.000 claims description 38
- 101150066717 Rara gene Proteins 0.000 claims description 37
- 239000003795 chemical substances by application Substances 0.000 claims description 37
- 108090000623 proteins and genes Proteins 0.000 claims description 34
- 102100038069 Interferon regulatory factor 8 Human genes 0.000 claims description 29
- 102100023606 Retinoic acid receptor alpha Human genes 0.000 claims description 25
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 claims description 24
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 claims description 24
- 239000008280 blood Substances 0.000 claims description 24
- 210000004369 blood Anatomy 0.000 claims description 24
- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 21
- 230000014509 gene expression Effects 0.000 claims description 21
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 claims description 21
- 108020004414 DNA Proteins 0.000 claims description 19
- 238000003559 RNA-seq method Methods 0.000 claims description 19
- -1 LSD1 inhibitor Substances 0.000 claims description 17
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 14
- 238000011529 RT qPCR Methods 0.000 claims description 13
- 239000003968 dna methyltransferase inhibitor Substances 0.000 claims description 13
- 108091005625 BRD4 Proteins 0.000 claims description 12
- 102100029895 Bromodomain-containing protein 4 Human genes 0.000 claims description 12
- 102000003676 Glucocorticoid Receptors Human genes 0.000 claims description 12
- 101001088883 Homo sapiens Lysine-specific demethylase 5B Proteins 0.000 claims description 12
- 101001025971 Homo sapiens Lysine-specific demethylase 6B Proteins 0.000 claims description 12
- 102100033247 Lysine-specific demethylase 5B Human genes 0.000 claims description 12
- 102100037461 Lysine-specific demethylase 6B Human genes 0.000 claims description 12
- 210000001185 bone marrow Anatomy 0.000 claims description 12
- 238000009396 hybridization Methods 0.000 claims description 12
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical group O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 claims description 11
- 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 claims description 11
- 229940126190 DNA methyltransferase inhibitor Drugs 0.000 claims description 11
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims description 11
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 11
- 229960002756 azacitidine Drugs 0.000 claims description 11
- 229960003787 sorafenib Drugs 0.000 claims description 11
- 230000004927 fusion Effects 0.000 claims description 10
- 102100038970 Histone-lysine N-methyltransferase EZH2 Human genes 0.000 claims description 9
- 101000882127 Homo sapiens Histone-lysine N-methyltransferase EZH2 Proteins 0.000 claims description 9
- 239000003276 histone deacetylase inhibitor Substances 0.000 claims description 9
- 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 claims description 8
- 102000040945 Transcription factor Human genes 0.000 claims description 8
- 108091023040 Transcription factor Proteins 0.000 claims description 8
- 230000003321 amplification Effects 0.000 claims description 8
- 229960003603 decitabine Drugs 0.000 claims description 8
- 239000003534 dna topoisomerase inhibitor Substances 0.000 claims description 8
- 238000003199 nucleic acid amplification method Methods 0.000 claims description 8
- 229940044693 topoisomerase inhibitor Drugs 0.000 claims description 8
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 claims description 7
- WBKCKEHGXNWYMO-UHFFFAOYSA-N 3-[[2-(2-pyridinyl)-6-(1,2,4,5-tetrahydro-3-benzazepin-3-yl)-4-pyrimidinyl]amino]propanoic acid ethyl ester Chemical compound N=1C(NCCC(=O)OCC)=CC(N2CCC3=CC=CC=C3CC2)=NC=1C1=CC=CC=N1 WBKCKEHGXNWYMO-UHFFFAOYSA-N 0.000 claims description 7
- 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 claims description 7
- 230000005971 DNA damage repair Effects 0.000 claims description 7
- 102100039489 Histone-lysine N-methyltransferase, H3 lysine-79 specific Human genes 0.000 claims description 7
- 101000963360 Homo sapiens Histone-lysine N-methyltransferase, H3 lysine-79 specific Proteins 0.000 claims description 7
- 229940123628 Lysine (K)-specific demethylase 1A inhibitor Drugs 0.000 claims description 7
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 7
- 239000012661 PARP inhibitor Substances 0.000 claims description 7
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 claims description 7
- 229940079156 Proteasome inhibitor Drugs 0.000 claims description 7
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 claims description 7
- 239000011724 folic acid Substances 0.000 claims description 7
- 229960000304 folic acid Drugs 0.000 claims description 7
- 235000019152 folic acid Nutrition 0.000 claims description 7
- 229940124302 mTOR inhibitor Drugs 0.000 claims description 7
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 claims description 7
- 239000003207 proteasome inhibitor Substances 0.000 claims description 7
- 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 claims description 6
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 claims description 6
- 229960000975 daunorubicin Drugs 0.000 claims description 6
- 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 claims description 6
- 108091008726 retinoic acid receptors α Proteins 0.000 claims description 6
- 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 claims description 5
- 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 claims description 5
- 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 5
- 238000000636 Northern blotting Methods 0.000 claims description 5
- 102000001708 Protein Isoforms Human genes 0.000 claims description 5
- 108010029485 Protein Isoforms Proteins 0.000 claims description 5
- 229940122954 Transcription factor inhibitor Drugs 0.000 claims description 5
- 229940121372 histone deacetylase inhibitor Drugs 0.000 claims description 5
- 229960000908 idarubicin Drugs 0.000 claims description 5
- 108010051621 interferon regulatory factor-8 Proteins 0.000 claims description 5
- 229960000485 methotrexate Drugs 0.000 claims description 5
- CVWXJKQAOSCOAB-UHFFFAOYSA-N quizartinib Chemical compound O1C(C(C)(C)C)=CC(NC(=O)NC=2C=CC(=CC=2)C=2N=C3N(C4=CC=C(OCCN5CCOCC5)C=C4S3)C=2)=N1 CVWXJKQAOSCOAB-UHFFFAOYSA-N 0.000 claims description 5
- 229950001626 quizartinib Drugs 0.000 claims description 5
- 229960000684 cytarabine Drugs 0.000 claims description 4
- 102100026810 Cyclin-dependent kinase 7 Human genes 0.000 claims description 3
- 101000911952 Homo sapiens Cyclin-dependent kinase 7 Proteins 0.000 claims description 3
- 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 claims description 3
- 229950010895 midostaurin Drugs 0.000 claims description 3
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims description 3
- 229960002594 arsenic trioxide Drugs 0.000 claims description 2
- 229960004618 prednisone Drugs 0.000 claims description 2
- 101001032345 Homo sapiens Interferon regulatory factor 8 Proteins 0.000 claims 24
- 101001112293 Homo sapiens Retinoic acid receptor alpha Proteins 0.000 claims 24
- 229940125888 CDK7 inhibitor Drugs 0.000 claims 7
- OBJNFLYHUXWUPF-IZZDOVSWSA-N n-[3-[[5-chloro-4-(1h-indol-3-yl)pyrimidin-2-yl]amino]phenyl]-4-[[(e)-4-(dimethylamino)but-2-enoyl]amino]benzamide Chemical compound C1=CC(NC(=O)/C=C/CN(C)C)=CC=C1C(=O)NC1=CC=CC(NC=2N=C(C(Cl)=CN=2)C=2C3=CC=CC=C3NC=2)=C1 OBJNFLYHUXWUPF-IZZDOVSWSA-N 0.000 claims 7
- 239000003719 aurora kinase inhibitor Substances 0.000 claims 5
- 229940123877 Aurora kinase inhibitor Drugs 0.000 claims 3
- 102000002027 Tuberin Human genes 0.000 claims 2
- 108050009309 Tuberin Proteins 0.000 claims 2
- 229940122429 Tubulin inhibitor Drugs 0.000 claims 2
- SZCZSKMCTGEJKI-UHFFFAOYSA-N tuberin Natural products COC1=CC=C(C=CNC=O)C=C1 SZCZSKMCTGEJKI-UHFFFAOYSA-N 0.000 claims 2
- 102000004000 Aurora Kinase A Human genes 0.000 claims 1
- 108090000461 Aurora Kinase A Proteins 0.000 claims 1
- DNVXATUJJDPFDM-KRWDZBQOSA-N JQ1 Chemical compound N([C@@H](CC(=O)OC(C)(C)C)C1=NN=C(N1C=1SC(C)=C(C)C=11)C)=C1C1=CC=C(Cl)C=C1 DNVXATUJJDPFDM-KRWDZBQOSA-N 0.000 claims 1
- 229960005549 JQ1 Drugs 0.000 claims 1
- 238000000034 method Methods 0.000 description 74
- 150000001875 compounds Chemical class 0.000 description 63
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 52
- 238000002560 therapeutic procedure Methods 0.000 description 43
- 230000014759 maintenance of location Effects 0.000 description 35
- 201000010099 disease Diseases 0.000 description 34
- 239000013610 patient sample Substances 0.000 description 31
- 230000004043 responsiveness Effects 0.000 description 30
- 230000000694 effects Effects 0.000 description 23
- 230000004044 response Effects 0.000 description 22
- 238000011292 agonist therapy Methods 0.000 description 20
- 208000035475 disorder Diseases 0.000 description 18
- 150000003839 salts Chemical class 0.000 description 18
- 230000001225 therapeutic effect Effects 0.000 description 17
- 238000012360 testing method Methods 0.000 description 16
- 238000001353 Chip-sequencing Methods 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 239000008194 pharmaceutical composition Substances 0.000 description 12
- 230000035945 sensitivity Effects 0.000 description 12
- 230000002195 synergetic effect Effects 0.000 description 12
- 210000001519 tissue Anatomy 0.000 description 12
- 238000003556 assay Methods 0.000 description 11
- 239000011324 bead Substances 0.000 description 11
- 239000003550 marker Substances 0.000 description 11
- 208000024891 symptom Diseases 0.000 description 11
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 10
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 10
- 239000013543 active substance Substances 0.000 description 10
- 239000000872 buffer Substances 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 230000001965 increasing effect Effects 0.000 description 10
- 239000012453 solvate Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 9
- 239000005557 antagonist Substances 0.000 description 9
- 238000002648 combination therapy Methods 0.000 description 9
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 8
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 8
- 238000009826 distribution Methods 0.000 description 8
- 239000008188 pellet Substances 0.000 description 8
- 108090000064 retinoic acid receptors Proteins 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000006228 supernatant Substances 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 241000220317 Rosa Species 0.000 description 7
- 239000007983 Tris buffer Substances 0.000 description 7
- 230000027455 binding Effects 0.000 description 7
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- 230000037406 food intake Effects 0.000 description 7
- 210000000056 organ Anatomy 0.000 description 7
- 230000036961 partial effect Effects 0.000 description 7
- 239000002953 phosphate buffered saline Substances 0.000 description 7
- 102000003702 retinoic acid receptors Human genes 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 6
- 230000001028 anti-proliverative effect Effects 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000002512 chemotherapy Methods 0.000 description 6
- 238000002487 chromatin immunoprecipitation Methods 0.000 description 6
- 235000012631 food intake Nutrition 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 229930002330 retinoic acid Natural products 0.000 description 6
- 238000012163 sequencing technique Methods 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 238000001574 biopsy Methods 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 235000013305 food Nutrition 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 230000002068 genetic effect Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 229960001727 tretinoin Drugs 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 108091007767 MALAT1 Proteins 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 102000034527 Retinoid X Receptors Human genes 0.000 description 4
- 108010038912 Retinoid X Receptors Proteins 0.000 description 4
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 150000007523 nucleic acids Chemical class 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 230000001717 pathogenic effect Effects 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 238000013268 sustained release Methods 0.000 description 4
- 239000012730 sustained-release form Substances 0.000 description 4
- 235000019155 vitamin A Nutrition 0.000 description 4
- 239000011719 vitamin A Substances 0.000 description 4
- 229940045997 vitamin a Drugs 0.000 description 4
- 239000011534 wash buffer Substances 0.000 description 4
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 3
- 108010033040 Histones Proteins 0.000 description 3
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 3
- 102000043138 IRF family Human genes 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 229960001445 alitretinoin Drugs 0.000 description 3
- 210000000601 blood cell Anatomy 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 238000006243 chemical reaction Methods 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
- 230000002596 correlated effect Effects 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 238000011393 cytotoxic chemotherapy Methods 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000012139 lysis buffer Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- NSQSAUGJQHDYNO-UHFFFAOYSA-N n-[(4,6-dimethyl-2-oxo-1h-pyridin-3-yl)methyl]-3-[ethyl(oxan-4-yl)amino]-2-methyl-5-[4-(morpholin-4-ylmethyl)phenyl]benzamide Chemical compound C=1C(C=2C=CC(CN3CCOCC3)=CC=2)=CC(C(=O)NCC=2C(NC(C)=CC=2C)=O)=C(C)C=1N(CC)C1CCOCC1 NSQSAUGJQHDYNO-UHFFFAOYSA-N 0.000 description 3
- 238000010606 normalization Methods 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 238000004393 prognosis Methods 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 238000011002 quantification Methods 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 230000004797 therapeutic response Effects 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 238000011269 treatment regimen Methods 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 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
- 239000012664 BCL-2-inhibitor Substances 0.000 description 2
- 229940123711 Bcl2 inhibitor Drugs 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010057248 Cell death Diseases 0.000 description 2
- 108091026890 Coding region Proteins 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 238000001712 DNA sequencing Methods 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 208000034951 Genetic Translocation Diseases 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 206010022773 Intracranial pressure increased Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 2
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 238000011088 calibration curve Methods 0.000 description 2
- 229910052799 carbon Chemical group 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 2
- 210000000349 chromosome Anatomy 0.000 description 2
- 238000002591 computed tomography Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 230000002380 cytological effect Effects 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 2
- 229940043264 dodecyl sulfate Drugs 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 230000009786 epithelial differentiation Effects 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 238000009093 first-line therapy Methods 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 238000011134 hematopoietic stem cell transplantation Methods 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 229940075628 hypomethylating agent Drugs 0.000 description 2
- 239000002955 immunomodulating agent Substances 0.000 description 2
- 229940121354 immunomodulator Drugs 0.000 description 2
- 238000001114 immunoprecipitation Methods 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000006651 lactation Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 108091070501 miRNA Proteins 0.000 description 2
- 239000002679 microRNA Substances 0.000 description 2
- 239000011325 microbead Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 210000000066 myeloid cell Anatomy 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 238000013188 needle biopsy Methods 0.000 description 2
- 238000007481 next generation sequencing Methods 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 229920002113 octoxynol Polymers 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 230000032696 parturition Effects 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 210000005259 peripheral blood Anatomy 0.000 description 2
- 239000011886 peripheral blood Substances 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000004492 retinoid derivatives Chemical class 0.000 description 2
- 238000010839 reverse transcription Methods 0.000 description 2
- 210000003296 saliva Anatomy 0.000 description 2
- 238000013077 scoring method Methods 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 238000011301 standard therapy Methods 0.000 description 2
- 238000013517 stratification Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 210000001138 tear Anatomy 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 229960001183 venetoclax Drugs 0.000 description 2
- LQBVNQSMGBZMKD-UHFFFAOYSA-N venetoclax Chemical compound C=1C=C(Cl)C=CC=1C=1CC(C)(C)CCC=1CN(CC1)CCN1C(C=C1OC=2C=C3C=CNC3=NC=2)=CC=C1C(=O)NS(=O)(=O)C(C=C1[N+]([O-])=O)=CC=C1NCC1CCOCC1 LQBVNQSMGBZMKD-UHFFFAOYSA-N 0.000 description 2
- 238000003260 vortexing Methods 0.000 description 2
- LXFOLMYKSYSZQS-XKHGBIBOSA-N (2R,3R,4S,5R)-2-(6-aminopurin-9-yl)-5-[[[3-[2-(6-tert-butyl-1H-benzimidazol-2-yl)ethyl]cyclobutyl]-propan-2-ylamino]methyl]oxolane-3,4-diol Chemical compound CC(C)(C)C1=CC=C2NC(CCC3CC(C3)N(C[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)C(C)C)=NC2=C1 LXFOLMYKSYSZQS-XKHGBIBOSA-N 0.000 description 1
- YAMSXCOVJUUMCT-FCHUYYIVSA-N 1-(4-methyl-1-piperazinyl)-2-[[(1R,2S)-2-(4-phenylmethoxyphenyl)cyclopropyl]amino]ethanone Chemical compound C1CN(C)CCN1C(=O)CN[C@H]1[C@H](C=2C=CC(OCC=3C=CC=CC=3)=CC=2)C1 YAMSXCOVJUUMCT-FCHUYYIVSA-N 0.000 description 1
- HYOAGWAIGJXNQH-UHFFFAOYSA-N 1-bromo-1-chloropropane Chemical compound CCC(Cl)Br HYOAGWAIGJXNQH-UHFFFAOYSA-N 0.000 description 1
- DMIDPTCQPIJYFE-UHFFFAOYSA-N 1-isoquinolin-6-yl-3-(2-oxo-2-pyrrolidin-1-ylethyl)urea Chemical compound C=1C=C2C=NC=CC2=CC=1NC(=O)NCC(=O)N1CCCC1 DMIDPTCQPIJYFE-UHFFFAOYSA-N 0.000 description 1
- 108020004463 18S ribosomal RNA Proteins 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- QOECJCJVIMVJGX-UHFFFAOYSA-N 2-cyclohexyl-6-methoxy-N-(1-propan-2-yl-4-piperidinyl)-7-[3-(1-pyrrolidinyl)propoxy]-4-quinazolinamine Chemical compound N1=C(C2CCCCC2)N=C2C=C(OCCCN3CCCC3)C(OC)=CC2=C1NC1CCN(C(C)C)CC1 QOECJCJVIMVJGX-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- DVGKRPYUFRZAQW-UHFFFAOYSA-N 3 prime Natural products CC(=O)NC1OC(CC(O)C1C(O)C(O)CO)(OC2C(O)C(CO)OC(OC3C(O)C(O)C(O)OC3CO)C2O)C(=O)O DVGKRPYUFRZAQW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 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
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- JCKGSPAAPQRPBW-OAQYLSRUSA-N 8-fluoro-n-[(2r)-1-oxo-1-pyrrolidin-1-yl-3-[3-(trifluoromethyl)phenyl]propan-2-yl]-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide Chemical compound C([C@@H](NS(=O)(=O)C=1C=C(C=2CNCCC=2C=1)F)C(=O)N1CCCC1)C1=CC=CC(C(F)(F)F)=C1 JCKGSPAAPQRPBW-OAQYLSRUSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 102100030379 Acyl-coenzyme A synthetase ACSM2A, mitochondrial Human genes 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000000058 Anaplasia Diseases 0.000 description 1
- 206010003178 Arterial thrombosis Diseases 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 208000018240 Bone Marrow Failure disease Diseases 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 206010006002 Bone pain Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 102100033641 Bromodomain-containing protein 2 Human genes 0.000 description 1
- 102100033642 Bromodomain-containing protein 3 Human genes 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
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 108010077544 Chromatin Proteins 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
- 206010010774 Constipation Diseases 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
- 102000053602 DNA Human genes 0.000 description 1
- 102000052510 DNA-Binding Proteins Human genes 0.000 description 1
- 108700020911 DNA-Binding Proteins Proteins 0.000 description 1
- 206010012455 Dermatitis exfoliative Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-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
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 108010067770 Endopeptidase K Proteins 0.000 description 1
- 244000148064 Enicostema verticillatum Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 206010015218 Erythema multiforme Diseases 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 208000031969 Eye Hemorrhage Diseases 0.000 description 1
- 102000001690 Factor VIII Human genes 0.000 description 1
- 108010054218 Factor VIII Proteins 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
- 239000004471 Glycine Substances 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 101100054737 Homo sapiens ACSM2A gene Proteins 0.000 description 1
- 101000871850 Homo sapiens Bromodomain-containing protein 2 Proteins 0.000 description 1
- 101000871851 Homo sapiens Bromodomain-containing protein 3 Proteins 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102100039905 Isocitrate dehydrogenase [NADP] cytoplasmic Human genes 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
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 102100025169 Max-binding protein MNT Human genes 0.000 description 1
- 102000000490 Mediator Complex Human genes 0.000 description 1
- 108010080991 Mediator Complex Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010027626 Milia Diseases 0.000 description 1
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 1
- 229910002651 NO3 Inorganic materials 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
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 108700026244 Open Reading Frames Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 108020002230 Pancreatic Ribonuclease Proteins 0.000 description 1
- 102000005891 Pancreatic ribonuclease Human genes 0.000 description 1
- 206010033661 Pancytopenia Diseases 0.000 description 1
- 208000006994 Precancerous Conditions Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000006193 Pulmonary infarction Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 206010042033 Stevens-Johnson syndrome Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010044223 Toxic epidermal necrolysis Diseases 0.000 description 1
- 231100000087 Toxic epidermal necrolysis Toxicity 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- 239000007984 Tris EDTA buffer Substances 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical group [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 239000000443 aerosol Substances 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
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- GGCUJPCCTQNTJF-FRCNGJHJSA-N all-trans-4-oxoretinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)C(=O)CCC1(C)C GGCUJPCCTQNTJF-FRCNGJHJSA-N 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000019552 anatomical structure morphogenesis Effects 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940124650 anti-cancer therapies Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 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
- 125000004429 atom Chemical group 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000005441 aurora Substances 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid 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
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000007469 bone scintigraphy Methods 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000002458 cell surface marker Substances 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 210000003483 chromatin Anatomy 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000011254 conventional chemotherapy Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 208000024389 cytopenia Diseases 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000005315 distribution function Methods 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000008406 drug-drug interaction Effects 0.000 description 1
- 230000037336 dry skin Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000012149 elution buffer Substances 0.000 description 1
- 238000009558 endoscopic ultrasound Methods 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- 230000008556 epithelial cell proliferation Effects 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000010437 erythropoiesis Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 208000004526 exfoliative dermatitis Diseases 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 230000002550 fecal effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 150000004687 hexahydrates Chemical class 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- 210000003917 human chromosome Anatomy 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 239000012133 immunoprecipitate Substances 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 230000010468 interferon response Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 238000007885 magnetic separation Methods 0.000 description 1
- 238000002826 magnetic-activated cell sorting Methods 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- LRPCLTPZMUIPFK-UHFFFAOYSA-N methane;sulfuric acid Chemical compound C.OS(O)(=O)=O LRPCLTPZMUIPFK-UHFFFAOYSA-N 0.000 description 1
- 238000001531 micro-dissection Methods 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- BASFYRLYJAZPPL-UONOGXRCSA-N n-[(1r,2s)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound N([C@@H]1C[C@H]1C=1C=CC=CC=1)C1CCNCC1 BASFYRLYJAZPPL-UONOGXRCSA-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
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000000771 oncological effect Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 238000011499 palliative surgery Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000002093 peripheral effect Effects 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
- 230000002688 persistence Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000005547 pivalate group Chemical group 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- 230000007575 pulmonary infarction Effects 0.000 description 1
- 210000004915 pus Anatomy 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 231100000916 relative toxicity Toxicity 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 102000027483 retinoid hormone receptors Human genes 0.000 description 1
- 108091008679 retinoid hormone receptors Proteins 0.000 description 1
- 229960003471 retinol Drugs 0.000 description 1
- 235000020944 retinol Nutrition 0.000 description 1
- 239000011607 retinol Substances 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000010079 rubber tapping Methods 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 108020003113 steroid hormone receptors Proteins 0.000 description 1
- 102000005969 steroid hormone receptors Human genes 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 210000003537 structural cell Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 208000011580 syndromic disease Diseases 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
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 102000004217 thyroid hormone receptors Human genes 0.000 description 1
- 108090000721 thyroid hormone receptors Proteins 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
- 238000011200 topical administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 108091006107 transcriptional repressors Proteins 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 229910052722 tritium Chemical group 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 230000009750 upstream signaling Effects 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/25—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids with polyoxyalkylated alcohols, e.g. esters of polyethylene glycol
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- 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
- A61K31/69—Boron compounds
-
- 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
- A61K31/695—Silicon compounds
-
- 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
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- 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
-
- 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
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/36—Arsenic; Compounds thereof
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
Description
本出願は、2016年4月8日に出願された米国特許仮出願第62/320,352号の優先権を主張し、その開示は、その内容全体が参照により本明細書に組み込まれる。
a.対象由来の病的な細胞の試料中に存在することが以前に決定されたIRF8 mRNAレベルに基づいて、対象がタミバロテン感受性型の疾患を有するかどうかを診断こと、及び
b.疾患を治療するのに有効な量のタミバロテンを対象に投与すること
を含む。
本出願では、文脈から明らかでない限り、(i)用語「a」は「少なくとも1つ」を意味すると理解され得、(ii)用語「または」は「及び/または」を意味すると理解され得、(iii)用語「含む(comprising)」及び「含む(including)」は、それ自体で提示されるか1つまたは複数のさらなる成分またはステップとともに提示されるかを問わず、記載された成分またはステップを包含すると理解され得、(iv)用語「約」及び「およそ」は、当業者に理解されるように、標準的な変動を認めると理解され得、(v)範囲が提供される場合は、終点も含まれる。
[発明を実施するための形態]
レチノイン酸受容体サブタイプアルファ(RARA)は、アンタゴニストが結合していない、または結合している場合に転写レプレッサーとして作用し、アゴニスト結合状況で遺伝子アクチベーターとして作用する、核内ホルモン受容体である。RARAの天然リガンドはオールトランスレチノイン酸(ATRA)としても知られるレチノイン酸であり、これは、ビタミンAから生成される。
エンハンサーまたはスーパーエンハンサーの特定は、当技術分野で既知の様々な方法によって、例えば、Cell 2013,155,934-947及びPCT/US2013/066957(これらの両方は、参照により本明細書に組み込まれる)に記載されているように達成することができる。いくつかの実施形態では、スーパーエンハンサーの特定は、患者のがん試料から(例えば、生検から)細胞性物質及びDNAを得ることによって達成される。エンハンサー測定に関する重要な測定基準は、2つの次元、すなわち、ゲノムマーカー(例えば、H3K27Ac)が隣接して検出されるDNAの長さ、及び規模を構成するDNAのスパンに沿った各塩基対におけるゲノムマーカーのコンパイルされた発生率に生じる。長さ及び規模の解析の積分によって生じる曲線下面積(「AUC」)の測定は、エンハンサーの強度を決定する。対象がRARAアゴニスト(例えば、タミバロテン)に応答性であるかどうかを決定するために本発明の一態様で使用されるのは、対照と比較したIRF8またはRARAスーパーエンハンサーの強度である。本明細書を考慮すれば、ゲノムマーカーが検出されるDNAの長さがIRF8またはRARAと対照の両方について同じである場合、対照に対するIRF8またはRARAスーパーエンハンサーの規模の比は強度と等しく、これも対象がRARAアゴニストに対して応答性であるかどうかを決定するために使用できることが、当業者に容易に明らかになるであろう。いくつかの実施形態では、他の試料と比較する前に、細胞におけるIRF8またはRARAエンハンサーの強度が正規化される。正規化は、すべての細胞において同様のレベルで存在する遍在性のスーパーエンハンサーまたはエンハンサーを含むことが知られている同じ細胞内の領域に対して比較することによって達成される。そのような遍在性スーパーエンハンサー領域の一例は、MALATlスーパーエンハンサー遺伝子座(chr11:65263724~65266724)(ゲノムビルドhg19)である。
いくつかの実施形態では、RARAアゴニストに対する感度を決定するために、IFR8 mRNAレベルをスーパーエンハンサーの強度または順位ランクの代わりに使用することができる。IRF8 mRNAを定量化することができ、これは、その遺伝子座におけるスーパーエンハンサー強度と非常に相関する(図10)。本発明者らは、IRF8をコードするmRNA転写産物はRARAアゴニストに対する感度と相関すると判断し(図8)、したがって、いくつかの実施形態では、RARAアゴニストに応答するであろう細胞を特定するためにIRF8 mRNAレベルを使用することができる。
本開示の方法は、スーパーエンハンサーとがんにおいて閾値レベル以上であるIRF8またはIRF8 mRNAレベルとの関連を特徴とする任意のがんを治療するのに有用である。スーパーエンハンサー関連IRF8遺伝子は、特定のタイプのがんにおいて他のがんよりも広く認められ得る。いくつかの実施形態では、スーパーエンハンサー関連IRF8遺伝子は、非APL AML及びMDSにおいて他のがんまたは前がん性状態よりも広く認められ得る。
スーパーエンハンサーレベルを有するとして特定された患者を治療するRARAアゴニストの選択は、当技術分野で既知の任意のRARAアゴニストから行うことができる。本発明の方法で利用するRARAアゴニストはRARAに対して特異的であり、且つ他の形態のRaR、例えば、RaR -β及びRaR-γに対して有意に低い(少なくともl0倍低い、少なくともl00倍低い、少なくとも1,000倍低い、少なくとも10,000倍低い、少なくとも100,000倍低い)アゴニスト活性を有することが好ましい。
マーカー及び特徴づけ
いくつかの実施形態では、RARAアゴニスト療法が、本開示に従って、本明細書に記載の1または複数の患者(例えば、患者集団)に施される。
一般に、本発明に従って使用される各活性薬剤(例えば、タミバロテン)は、適正な医療行為と矛盾がなく且つ関連する薬剤(複数可)及び対象に適している医薬組成物及び投薬レジメンを使用して、製剤化され、用量決定され、治療有効量で投与される。原則として、治療用組成物は、限定はされないが、経口、粘膜、吸入によるもの、局所、頬側、経鼻、直腸または非経口(例えば、静脈内、注入、腫瘍内、結節内、皮下、腹腔内、筋肉内、皮内、経皮もしくは他の種類の投与)を含めた、当技術分野で既知の任意の適切な方法によって投与することができる。いくつかの実施形態では、RARAアゴニスト(例えば、タミバロテン)は経口的に投与される。
本明細書で使用する場合、医薬組成物は、化合物、例えばタミバロテンと他の化学成分、例えば、担体、安定化剤、希釈剤、分散剤、懸濁化剤、増粘剤及び/または賦形剤との混合物を指す。医薬組成物は、生物への化合物の投与を容易にする。化合物を含む医薬組成物は、(限定されないが、静脈内、経口、直腸、エアロゾル、非経口、眼部、肺、経皮、腟、耳、経鼻及び局所的投与を含めた)、当技術分野で既知の任意の従来の形態及び経路によって、治療有効量で投与され得る。
本開示を読めば、ある種の実施形態では、本明細書に記載のRARAアゴニスト(例えば、タミバロテン)を、例えば、化学療法剤、他の免疫調節剤の投与、放射線療法、高周波数超音波療法、手術、がん治療についてFDAが承認した療法などを含めた他の抗がん療法と組み合わせることができることを当業者は容易に認識するであろう。
1種または複数のIRF8バイオマーカーを検出するための1種または複数の試薬を含むキットをキットで提供することができる。ある場合には、キットは、がんを罹患しており、且つ閾値レベル以上である強度もしくは順位ランクを有するIRF8遺伝子と関連するスーパーエンハンサー、または参照(例えば、閾値レベル)以上であるIRF8 mRNAレベルを有すると決定された対象においてRARAアゴニスト(例えば、タミバロテン)を使用するための指示書をともなう記載された挿入物またはラベルを含む、パッケージ化された本発明の医薬組成物を含む。上で詳細に記載されているように、閾値レベルは、医薬組成物が治療について示されるものと同じ疾患を罹患していると診断された対象、または医薬組成物が治療について示されるものと同じ疾患の細胞株もしくは異種移植モデルのいずれか由来の試料の集団において、決定される。指示書は、RARAアゴニストを含む容器に接着または付着させることができる。あるいは、指示書及びRARAアゴニストを含む容器は互いに分離されてもよいが、単一のキット、パッケージ、箱または他のタイプの容器中に一緒に存在する。
本発明者らは、タミバロテンに対する感度についていくつかのAML細胞株を以前に試験し、RARAスーパーエンハンサーの強度、RARAスーパーエンハンサー強度の順位及びRARA mRNAレベルのそれぞれと感度が非常によく相関することを示した。これは、以下に記載のように行った。
AML細胞株の結果は、RNA-Seqアッセイにおいて15.5から190TPMの間(すなわち、log2(4.03)からlog2(7.57)の間)のカットオフ値を示唆する。IRF mRNAレベルの分布を調べるために、及びカットオフ値に基づく保有率カットオフを決定するために、(Stanford Universityの好意により提供された)AML患者試料の集団を選択した。その集団にAML細胞株を加え、次いで、順位序列化グラフを生成した。図3は、組み合わせた患者試料/AML細胞株集団におけるIRF8 mRNAレベルの順位序列化分布を示す。本発明者らは、25%の保有率カットオフがおよそlog2(7)のIRF mRNA値に対応すると判断した。
次に、AML細胞株及び患者集団においてIRF8 mRNAレベルとRARA mRNAレベルを比較して、相関を決定した。図4は、タミバロテンに応答したいくつかの細胞株は、比較的低いRARA mRNAを有するが、高IRF8 mRNAレベルを有することを示す。図5は、患者のサブセットも高IRF8 mRNAレベルを示すが、比較的低いRARA mRNAレベルを示し、逆もまた同じであることを示す。これは、患者においてIRF8 mRNAとRARA mRNAの両方を測定すること、及びいずれかのmRNAレベルが閾値を超える場合に、RARAアゴニスト、例えばタミバロテンによる治療のための患者を選択することが、治療可能な患者集団を最適化することができるという考えを支持する。
次に、以下のように、いくつかのAML細胞株及び患者試料においてIRF8エンハンサー強度を調べた。
IRF8エンハンサーの定量化及びChIP-seqとRNA-seqデータの相関:クオンタイル正規化したRECOMBスコアを、IRF8と重複する、ユニバーサルマップでエンハンサーと呼ばれる領域(chr16:85862582~85990086)について、すべての患者にわたって使用した。これは、スピアマンの相関を使用するRSEMからの完全なIRF8遺伝子モデルについてのクオンタイル正規化したTPM発現の推定と相関した。RNA-seqとChIP-seqの両方を有する患者のみを使用した。細胞株で同じ解析を行ったが、APL細胞株は除外した。
BALB/cヌード免疫無防備状態マウスにおける異なるAML患者試料(AM8096、AM5512、AM7577及びAM7440)由来の異種移植モデルは、Crown Biosciences(Beijing、China)によって、本質的に以下のように調製される。
血液(8mL)を非APL AML患者から採取し、8mLのBD Vacutainer CPTクエン酸ナトリウムチューブに収集した。採血に続いて、チューブを8~10回手で軽く転倒させて、確実に抗凝血剤が十分に見られなくなるようにした。収集してから2時間以内に行う遠心分離の前に、チューブを直立させて室温で保存した。次いで血液試料を、1500~1800RCF(相対遠心力)で、室温(l8~25℃)で20分間遠心分離した。遠心分離後に、血液は層に分離した。ゲルプラグより下の下部層は、完全な下部にある赤色層(赤血球)及びこの上の薄い灰色の層(顆粒球及び密度溶液)である。ゲルプラグの真上は密度溶液の透明な層であり、次いで、白色層(単核細胞及び血小板)及び上部の黄色がかった層(血漿)であった。PBMCを含む白色層(1mLの体積まで)を遠心分離してからパスツールピペットで直ちに取り出した。必要に応じて、滴加し、続いて穏やかに手で反転させて混合する20%v/vのBloodStor(登録商標)凍結培地(BioLife Solutions)を含むクライオバイアル中でPBMCを保存することができる。
Biotek EL406を使用して、20~60,000細胞/mlを含む50μLの細胞培地を白色384ウェルNuncプレート(Thermo)に分配した。次いで、懸濁細胞には化合物を直ちに加えたが、接着細胞株には1時間与えて、化合物の添加より前にプレートの表面に再付着させた。タミバロテン及び試験する第2の薬剤をDMSOに溶解し、384ウェル化合物貯蔵プレート(Greiner)上にアレイ化させた。各化合物プレートに、それぞれ所与の細胞株に対する所与の化合物のEC50を中心とした5つの異なる用量でタミバロテン及び1つの第2の薬剤を加え、これによって、2つの薬剤について合計で25の異なる用量の組み合わせがもたらされた。
参考文献
1. Niederreither, K. & Dolle, P. Retinoic acid in development: towards an integrated view. Nat. Rev. Genet. 9, 541-553 (2008).
2. Chapuy, B. et al. Discovery and Characterization of Super-Enhancer-Associated Dependencies in Diffuse Large B Cell Lymphoma. Cancer Cell 24, 777-790 (2013).
3. Tamura, T., Kurotaki, D. & Koizumi, S. Regulation of myelopoiesis by the transcription factor IRF8. Int. J. Hematol. 101, 342-351 (2015).
4. Yang, J. et al. Cutting Edge: ^ff8 Regulates Bax Transcription In Vivo in Primary Myeloid Cells. J Immunol. 187, 4426-4430 (2011).
5. Pogosova-Agadjanyan, E. L. et al. The Prognostic Significance of IRF8 Transcripts in Adult Patients with Acute Myeloid Leukemia. PLoS ONE 8, e70812 (2013).
6. Sharma, A. et al. Constitutive 1IRF8 expression inhibits AML by activation of repressed immune response signaling. Leukemia 29, 157-168 (2015).
7. Smits, E. L. J. M., Anguille, S. & Berneman, Z. N. Interferon a may be back on track to treat acute myeloid leukemia. Oncolmmunology 2, e23619 (2013).
8. Chelbi-Alix, M. K. & Pelicano, L. Retinoic acid and interferon signaling cross talk in normal and RA-resistant APL cells. Leuk. 08876924 13, (1999).
9. Encode Project Consortium, An integrated encyclopedia of DNA elements in the human genome. Nature 489: 57-74 (2012).
10. SY-1425-P003: Effects of tamibarotene (SY-1425) on proliferation of Acute Myeloid Leukemia (AML) cell lines in comparison to all-trans retinoic acid (ATRA)
11. SY-1425-P006: Characterization of the RARA enhancer and RARa mRNA in AML patient samples and cell lines
Claims (65)
- 非急性前骨髄球性白血病急性骨髄性白血病(非APL AML)および骨髄異形成症候群(MDS)から選択されるがんを治療するための、タミバロテンと第2の治療剤とを含む組み合わせ物であって、前記組み合わせ物が、非APL AMLまたはMDSを有する対象に投与されることを特徴とし、前記対象から得られた生物試料におけるがん細胞が、IRF8バイオマーカー及び/またはRARAバイオマーカーを有すると決定され、
前記IRF8バイオマーカーが、上昇したIRF8 mRNAレベルの1つもしくは複数またはIRF8遺伝子と関連するスーパーエンハンサーの発現であるか、またはこれ含み、
前記RARAバイオマーカーが、上昇したRARA mRNAレベルの1つまたは複数またはRARA遺伝子と関連するスーパーエンハンサーの発現であるか、またはこれ含み、
前記第2の治療剤が、DNAメチルトランスフェラーゼ阻害剤、DNA合成酵素阻害剤、トポイソメラーゼ阻害剤、FLT3阻害剤、葉酸阻害剤、BRD4阻害剤、Znフィンガー転写因子阻害剤、GCR阻害剤、CDK7阻害剤、HDAC阻害剤、JMJD3/JARID1B阻害剤、EZH2阻害剤、LSD1阻害剤、プロテアソーム阻害剤、DNA損傷修復阻害剤、PARP阻害剤、mTOR阻害剤、DOT1L阻害剤、チューブリン阻害剤、PLK阻害剤またはオーロラキナーゼ阻害剤から選択される、
組み合わせ物。 - 前記がんが非APL AMLである、請求項1に記載の組み合わせ物。
- 前記がんがMDSである、請求項1に記載の組み合わせ物。
- 前記第2の治療剤が、DNAメチルトランスフェラーゼ阻害剤、DNA合成酵素阻害剤、トポイソメラーゼ阻害剤、FLT3阻害剤、葉酸阻害剤、BRD4阻害剤、Znフィンガー転写因子阻害剤、GCR阻害剤、CDK7阻害剤、HDAC阻害剤、JMJD3/JARID1B阻害剤、及びEZH2阻害剤から選択される、請求項1~3のいずれか一項に記載の組み合わせ物。
- 前記第2の治療剤が、LSD1阻害剤、プロテアソーム阻害剤、DNA損傷修復阻害剤、PARP阻害剤、mTOR阻害剤、DOT1L阻害剤、チューブリン阻害剤、PLK阻害剤、またはオーロラキナーゼ阻害剤から選択される、請求項1~3のいずれか一項に記載の組み合わせ物。
- 前記第2の治療剤が、DNAメチルトランスフェラーゼ阻害剤である、請求項1~3のいずれか一項に記載の組み合わせ物。
- 前記DNAメチルトランスフェラーゼ阻害剤が、アザシチジンまたはデシタビンである、請求項6に記載の組み合わせ物。
- 前記第2の治療剤がFLT3阻害剤である、請求項1~3のいずれか一項に記載の組み合わせ物。
- 前記FLT3阻害剤がソラフェニブである、請求項8に記載の組み合わせ物。
- 前記第2の治療剤がCDK7阻害剤である、請求項1~3のいずれか一項に記載の組み合わせ物。
- 前記上昇したIRF8 mRNAレベルおよび/または前記上昇したRARA mRNAレベルが、蛍光ハイブリダイゼーション、PCR、qPCR、qRT-PCR、RNAシークエンシング、RNAハイブリダイゼーション及びシグナル増幅、またはノーザンブロットを用いて独立して決定される、請求項1~3のいずれか一項に記載の組み合わせ物。
- 前記対象から得られた生物試料が、骨髄吸引液または全血である、請求項1~3のいずれか一項に記載の組み合わせ物。
- 前記骨髄吸引液または全血が、1またはそれ以上の成分を除去するために処理される、請求項12に記載の組み合わせ物。
- 前記全血が、末梢血単核細胞(PBMC)試料または富化PBMC試料を得るために処理される、請求項13に記載の組み合わせ物。
- 前記対象から得られた生物試料が、IRF8バイオマーカーを有すると判定されている、請求項1~3のいずれか一項に記載の組み合わせ物。
- IRF8 RNA転写産物が、インターフェロンコンセンサス配列結合タンパク質またはそのスプライスバリアントをコードするゲノムDNA配列から転写され、かつIRF8遺伝子のすべてまたは一部を含む遺伝子融合物を特に除外し、IRF8遺伝子がゲノムビルドhg19のchr16:85862582~85990086に位置する、請求項15に記載の組み合わせ物。
- 前記対象から得られた生物試料が、RARAバイオマーカーを有すると判定されている、請求項1~3のいずれか一項に記載の組み合わせ物。
- RARA RNA転写産物が、機能的なレチノイン酸受容体-α遺伝子をコードするゲノムDNA配列から転写され、かつRARA遺伝子のすべてまたは一部を含む遺伝子融合物を特に除外し、RARA遺伝子がchr17:38458152~38516681に位置する、請求項17に記載の組み合わせ物。
- 非APL AMLまたはMDSを治療するためのタミバロテンを含む組成物であって、前記組成物が、非APL AMLまたはMDSを有する対象に、第2の治療剤と組み合わせて投与されることを特徴とし、前記対象から得られた生物試料におけるがん細胞が、IRF8バイオマーカー及び/またはRARAバイオマーカーを有すると決定され、
前記IRF8バイオマーカーが、上昇したIRF8 mRNAレベルの1つもしくは複数またはIRF8遺伝子と関連するスーパーエンハンサーの発現であるか、またはこれ含み、
前記RARAバイオマーカーが、上昇したRARA mRNAレベルの1つまたは複数またはRARA遺伝子と関連するスーパーエンハンサーの発現であるか、またはこれ含み、
前記第2の治療剤が、アザシチジン、三酸化ヒ素、ミドスタウリン、シタラビン、ダウノルビシン、メトトレキサート、イダルビシン、ソラフェニブ、デシタビン、キザルチニブ、JQ1、プレドニゾン、SAHA及びGSKJ4から選択され、ここでは、
前記第2の治療剤がミドスタウリン、ソラフェニブまたはキザルチニブである場合、前記がんが上昇したFLT3 mRNAレベルを有するとさらに決定される場合にのみ前記薬剤が投与され、
前記第2の治療剤がプレドニゾンである場合、前記がんが上昇したGCRmRNAレベルを有するとさらに決定される場合にのみ前記薬剤が投与され、
前記第2の治療剤がGSKJ4である場合、前記がんが上昇したJMJD3及び/またはJARID1B mRNAレベルを有するとさらに決定される場合にのみ前記薬剤が投与される、組成物。 - 前記がんが非APL AMLである、請求項19に記載の組成物。
- 前記がんがMDSである、請求項19に記載の組成物。
- 前記上昇したIRF8 mRNAレベルおよび/または前記上昇したRARA mRNAレベルが、蛍光ハイブリダイゼーション、PCR、qPCR、qRT-PCR、RNAシークエンシング、RNAハイブリダイゼーション及びシグナル増幅、またはノーザンブロットを用いて独立して決定される、請求項19~21のいずれか一項に記載の組成物。
- 前記対象から得られた生物試料が、骨髄吸引液または全血である、請求項19~21のいずれか一項に記載の組成物。
- 前記骨髄吸引液または全血が、1またはそれ以上の成分を除去するために処理される、請求項23に記載の組成物。
- 前記全血が、末梢血単核細胞(PBMC)試料または富化PBMC試料を得るために処理される、請求項24に記載の組成物。
- 前記対象から得られた生物試料が、IRF8バイオマーカーを有すると判定されている、請求項19~21のいずれか一項に記載の組成物。
- IRF8 RNA転写産物が、インターフェロンコンセンサス配列結合タンパク質またはそのスプライスバリアントをコードするゲノムDNA配列から転写され、かつIRF8遺伝子のすべてまたは一部を含む遺伝子融合物を特に除外し、IRF8遺伝子がゲノムビルドhg19のchr16:85862582~85990086に位置する、請求項26に記載の組成物。
- 前記対象から得られた生物試料が、RARAバイオマーカーを有すると判定されている、請求項19~21のいずれか一項に記載の組成物。
- RARA RNA転写産物が、機能的なレチノイン酸受容体-α遺伝子をコードするゲノムDNA配列から転写され、かつRARA遺伝子のすべてまたは一部を含む遺伝子融合物を特に除外し、RARA遺伝子がchr17:38458152~38516681に位置する、請求項28に記載の組成物。
- 非APL AMLまたはMDSを治療するためのタミバロテンを含む組成物であって、前記組成物が、非APL AMLまたはMDSを有する対象に、第2の治療剤と組み合わせて投与されることを特徴とし、前記対象から得られた生物試料におけるがん細胞が、IRF8バイオマーカー及び/またはRARAバイオマーカーを有すると決定され、
前記IRF8バイオマーカーが、上昇したIRF8 mRNAレベルの1つもしくは複数またはIRF8遺伝子と関連するスーパーエンハンサーの発現であるか、またはこれ含み、
前記RARAバイオマーカーが、上昇したRARA mRNAレベルの1つまたは複数またはRARA遺伝子と関連するスーパーエンハンサーの発現であるか、またはこれ含み、
前記第2の治療剤が、DNAメチルトランスフェラーゼ阻害剤、DNA合成酵素阻害剤、トポイソメラーゼ阻害剤、FLT3阻害剤、葉酸阻害剤、BRD4阻害剤、Znフィンガー転写因子阻害剤、GCR阻害剤、CDK7阻害剤、HDAC阻害剤、JMJD3/JARID1B阻害剤、EZH2阻害剤、LSD1阻害剤、プロテアソーム阻害剤、DNA損傷修復阻害剤、PARP阻害剤、mTOR阻害剤、DOT1L阻害剤、チューブリン阻害剤、PLK阻害剤、またはオーロラキナーゼ阻害剤から選択される、組成物。 - 前記がんが非APL AMLである、請求項30に記載の組成物。
- 前記がんがMDSである、請求項30に記載の組成物。
- 前記第2の治療剤が、DNAメチルトランスフェラーゼ阻害剤、DNA合成酵素阻害剤、トポイソメラーゼ阻害剤、FLT3阻害剤、葉酸阻害剤、BRD4阻害剤、Znフィンガー転写因子阻害剤、GCR阻害剤、CDK7阻害剤、HDAC阻害剤、JMJD3/JARID1B阻害剤、及びEZH2阻害剤から選択される、請求項30~32のいずれか一項に記載の組成物。
- 前記第2の治療剤が、LSD1阻害剤、プロテアソーム阻害剤、DNA損傷修復阻害剤、PARP阻害剤、mTOR阻害剤、DOT1L阻害剤、チューブリン阻害剤、PLK阻害剤、またはオーロラキナーゼ阻害剤から選択される、請求項30~32のいずれか一項に記載の組成物。
- 前記第2の治療剤が、DNAメチルトランスフェラーゼ阻害剤である、請求項30~32のいずれか一項に記載の組成物。
- 前記DNAメチルトランスフェラーゼ阻害剤が、アザシチジンまたはデシタビンである、請求項35に記載の組成物。
- 前記第2の治療剤がFLT3阻害剤である、請求項30~32のいずれか一項に記載の組成物。
- 前記FLT3阻害剤がソラフェニブである、請求項37に記載の組成物。
- 前記第2の治療剤がCDK7阻害剤である、請求項30~32のいずれか一項に記載の組成物。
- 前記上昇したIRF8 mRNAレベルおよび/または前記上昇したRARA mRNAレベルが、蛍光ハイブリダイゼーション、PCR、qPCR、qRT-PCR、RNAシークエンシング、RNAハイブリダイゼーション及びシグナル増幅、またはノーザンブロットを用いて独立して決定される、請求項30~32のいずれか一項に記載の組成物。
- 前記対象から得られた生物試料が、骨髄吸引液または全血である、請求項30~32のいずれか一項に記載の組成物。
- 前記骨髄吸引液または全血が、1またはそれ以上の成分を除去するために処理される、請求項41に記載の組成物。
- 前記全血が、末梢血単核細胞(PBMC)試料または富化PBMC試料を得るために処理される、請求項42に記載の組成物。
- 前記対象から得られた生物試料が、IRF8バイオマーカーを有すると判定されている、請求項30~32のいずれか一項に記載の組成物。
- IRF8 RNA転写産物が、インターフェロンコンセンサス配列結合タンパク質またはそのスプライスバリアントをコードするゲノムDNA配列から転写され、かつIRF8遺伝子のすべてまたは一部を含む遺伝子融合物を特に除外し、IRF8遺伝子がゲノムビルドhg19のchr16:85862582~85990086に位置する、請求項44に記載の組成物。
- 前記対象から得られた生物試料が、RARAバイオマーカーを有すると判定されている、請求項30~32のいずれか一項に記載の組成物。
- RARA RNA転写産物が、機能的なレチノイン酸受容体-α遺伝子をコードするゲノムDNA配列から転写され、かつRARA遺伝子のすべてまたは一部を含む遺伝子融合物を特に除外し、RARA遺伝子がchr17:38458152~38516681に位置する、請求項46に記載の組成物。
- 非APL AMLまたはMDSを治療するための治療剤を含む組成物であって、前記組成物が、非APL AMLまたはMDSを有する対象に、タミバロテンと組み合わせて投与されることを特徴とし、前記対象から得られた生物試料におけるがん細胞が、IRF8バイオマーカー及び/またはRARAバイオマーカーを有すると決定され、
前記IRF8バイオマーカーが、上昇したIRF8 mRNAレベルの1つもしくは複数またはIRF8遺伝子と関連するスーパーエンハンサーの発現であるか、またはこれ含み、
前記RARAバイオマーカーが、上昇したRARA mRNAレベルの1つまたは複数またはRARA遺伝子と関連するスーパーエンハンサーの発現であるか、またはこれ含み、
前記治療剤が、DNAメチルトランスフェラーゼ阻害剤、DNA合成酵素阻害剤、トポイソメラーゼ阻害剤、FLT3阻害剤、葉酸阻害剤、BRD4阻害剤、Znフィンガー転写因子阻害剤、GCR阻害剤、CDK7阻害剤、HDAC阻害剤、JMJD3/JARID1B阻害剤、EZH2阻害剤、LSD1阻害剤、プロテアソーム阻害剤、DNA損傷修復阻害剤、PARP阻害剤、mTOR阻害剤、DOT1L阻害剤、チューブリン阻害剤、PLK阻害剤、またはオーロラキナーゼ阻害剤から選択される、組成物。 - 前記がんが非APL AMLである、請求項48に記載の組成物。
- 前記がんがMDSである、請求項48に記載の組成物。
- 前記治療剤が、DNAメチルトランスフェラーゼ阻害剤、DNA合成酵素阻害剤、トポイソメラーゼ阻害剤、FLT3阻害剤、葉酸阻害剤、BRD4阻害剤、Znフィンガー転写因子阻害剤、GCR阻害剤、CDK7阻害剤、HDAC阻害剤、JMJD3/JARID1B阻害剤、及びEZH2阻害剤から選択される、請求項48~50のいずれか一項に記載の組成物。
- 前記治療剤が、LSD1阻害剤、プロテアソーム阻害剤、DNA損傷修復阻害剤、PARP阻害剤、mTOR阻害剤、DOT1L阻害剤、チューブリン阻害剤、PLK阻害剤、またはオーロラキナーゼ阻害剤から選択される、請求項48~50のいずれか一項に記載の組成物。
- 前記治療剤が、DNAメチルトランスフェラーゼ阻害剤である、請求項30~32のいずれか一項に記載の組成物。
- 前記DNAメチルトランスフェラーゼ阻害剤が、アザシチジンまたはデシタビンである、請求項53に記載の組成物。
- 前記治療剤がFLT3阻害剤である、請求項48~50のいずれか一項に記載の組成物。
- 前記FLT3阻害剤がソラフェニブである、請求項55に記載の組成物。
- 前記治療剤がCDK7阻害剤である、請求項48~50のいずれか一項に記載の組成物。
- 前記上昇したIRF8 mRNAレベルおよび/または前記上昇したRARA mRNAレベルが、蛍光ハイブリダイゼーション、PCR、qPCR、qRT-PCR、RNAシークエンシング、RNAハイブリダイゼーション及びシグナル増幅、またはノーザンブロットを用いて独立して決定される、請求項48~50のいずれか一項に記載の組成物。
- 前記対象から得られた生物試料が、骨髄吸引液または全血である、請求項48~50のいずれか一項に記載の組成物。
- 前記骨髄吸引液または全血が、1またはそれ以上の成分を除去するために処理される、請求項59に記載の組成物。
- 前記全血が、末梢血単核細胞(PBMC)試料または富化PBMC試料を得るために処理される、請求項60に記載の組成物。
- 前記対象から得られた生物試料が、IRF8バイオマーカーを有すると判定されている、請求項48~50のいずれか一項に記載の組成物。
- IRF8 RNA転写産物が、インターフェロンコンセンサス配列結合タンパク質またはそのスプライスバリアントをコードするゲノムDNA配列から転写され、かつIRF8遺伝子のすべてまたは一部を含む遺伝子融合物を特に除外し、IRF8遺伝子がゲノムビルドhg19のchr16:85862582~85990086に位置する、請求項62に記載の組成物。
- 前記対象から得られた生物試料が、RARAバイオマーカーを有すると判定されている、請求項48~50のいずれか一項に記載の組成物。
- RARA RNA転写産物が、機能的なレチノイン酸受容体-α遺伝子をコードするゲノムDNA配列から転写され、かつRARA遺伝子のすべてまたは一部を含む遺伝子融合物を特に除外し、RARA遺伝子がchr17:38458152~38516681に位置する、請求項64に記載の組成物。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2021135461A JP7284224B2 (ja) | 2016-04-08 | 2021-08-23 | Aml及びmdsの治療のためのraraアゴニスト |
JP2023023318A JP2023057151A (ja) | 2016-04-08 | 2023-02-17 | Aml及びmdsの治療のためのraraアゴニスト |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662320352P | 2016-04-08 | 2016-04-08 | |
US62/320,352 | 2016-04-08 | ||
PCT/US2017/026657 WO2017177167A1 (en) | 2016-04-08 | 2017-04-07 | Rara agonists for the treatment of aml and mds |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021135461A Division JP7284224B2 (ja) | 2016-04-08 | 2021-08-23 | Aml及びmdsの治療のためのraraアゴニスト |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2019513758A JP2019513758A (ja) | 2019-05-30 |
JP7034085B2 true JP7034085B2 (ja) | 2022-03-11 |
Family
ID=58633103
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018553078A Active JP7034085B2 (ja) | 2016-04-08 | 2017-04-07 | Aml及びmdsの治療のためのraraアゴニスト |
JP2021135461A Active JP7284224B2 (ja) | 2016-04-08 | 2021-08-23 | Aml及びmdsの治療のためのraraアゴニスト |
JP2023023318A Pending JP2023057151A (ja) | 2016-04-08 | 2023-02-17 | Aml及びmdsの治療のためのraraアゴニスト |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021135461A Active JP7284224B2 (ja) | 2016-04-08 | 2021-08-23 | Aml及びmdsの治療のためのraraアゴニスト |
JP2023023318A Pending JP2023057151A (ja) | 2016-04-08 | 2023-02-17 | Aml及びmdsの治療のためのraraアゴニスト |
Country Status (11)
Country | Link |
---|---|
US (1) | US20240102106A1 (ja) |
EP (1) | EP3452032A1 (ja) |
JP (3) | JP7034085B2 (ja) |
KR (2) | KR20220148926A (ja) |
CN (2) | CN109310657B (ja) |
AU (2) | AU2017248187B2 (ja) |
BR (1) | BR112018070547A2 (ja) |
CA (1) | CA3020173A1 (ja) |
IL (2) | IL262156B2 (ja) |
MX (1) | MX2018012250A (ja) |
WO (1) | WO2017177167A1 (ja) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3277272B1 (en) | 2015-03-31 | 2021-08-04 | Syros Pharmaceuticals, Inc. | Methods of stratifying patients for treatment with retinoic acid receptor-agonists |
US9868994B2 (en) | 2016-04-08 | 2018-01-16 | Syros Pharmaceuticals, Inc. | Methods of stratifying patients for treatment with retinoic acid receptor-α agonists |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015101618A1 (en) | 2013-12-30 | 2015-07-09 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Combination of an arsenic compound and at least one retinoid for treating acute myeloid leukemia |
WO2016161107A1 (en) | 2015-03-31 | 2016-10-06 | Syros Pharmaceuticals, Inc. | METHODS OF STRATIFYING PATIENTS FOR TREATMENT WITH RETINOIC ACID RECEPTOR-α AGONISTS |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3580134D1 (de) | 1984-07-07 | 1990-11-22 | Shudo Koichi Prof Dr Chem | Benzoesaeurederivate. |
US5089509A (en) | 1988-09-15 | 1992-02-18 | Allergan, Inc. | Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity |
JP2752630B2 (ja) | 1988-03-29 | 1998-05-18 | 大鵬薬品工業株式会社 | 新規安息香酸誘導体及びその製造方法 |
US5759785A (en) | 1992-05-14 | 1998-06-02 | Baylor College Of Medicine | Method of identifying hormone antagonists and agonists |
US5455265A (en) | 1993-02-11 | 1995-10-03 | Allergan, Inc. | Method of treatment with compounds having selective agonist-like activity on RXR retinoid receptors |
US5824685A (en) | 1995-02-01 | 1998-10-20 | The Johns Hopkins University School Of Medicine | Method of preventing proliferation of retinal pigment epithelium by retinoic acid receptor agonists |
FR2739777B1 (fr) | 1995-10-11 | 1997-11-14 | Cird Galderma | Ligand antagoniste rar-gamma ou agoniste rar-alpha en tant qu'inhibiteur d'apoptose |
US5675024A (en) | 1995-11-22 | 1997-10-07 | Allergan | Aryl or heteroaryl amides of tetrahydronaphthalene, chroman, thiochroman and 1,2,3,4,-tetrahydroquinoline carboxylic acids, having an electron withdrawing substituent in the aromatic or heteroaromatic moiety, having retinoid-like biological activity |
US5965606A (en) | 1995-12-29 | 1999-10-12 | Allergan Sales, Inc. | Methods of treatment with compounds having RAR.sub.α receptor specific or selective activity |
HUP9902645A3 (en) | 1996-03-18 | 1999-12-28 | Eisai Co Ltd | Fused-ring carboxylic acid derivatives |
US5919970A (en) | 1997-04-24 | 1999-07-06 | Allergan Sales, Inc. | Substituted diaryl or diheteroaryl methanes, ethers and amines having retinoid agonist, antagonist or inverse agonist type biological activity |
CA2307613A1 (en) | 1997-10-22 | 1999-04-29 | Eisai Co., Ltd. | Retinoic acid agonist as a prophylactic and therapeutic agent for nephritis |
TWI281911B (en) | 2000-04-04 | 2007-06-01 | Allergan Inc | Treatment of tumors with RARalpha selective retinoid compounds in combination with other anti-tumor agents |
WO2007108272A1 (ja) * | 2006-03-23 | 2007-09-27 | Tmrc Co., Ltd. | 癌治療用キットおよび癌治療用医薬組成物 |
CN101495115A (zh) * | 2006-08-02 | 2009-07-29 | 健赞股份有限公司 | 组合治疗 |
KR20100016048A (ko) | 2007-03-30 | 2010-02-12 | 테무릭크 가부시키가이샤 | 타미바로텐 캡슐제 |
JP2010202553A (ja) * | 2009-03-02 | 2010-09-16 | Unitika Ltd | レチノイン酸受容体(rar)活性化剤 |
EP2417984B1 (en) * | 2009-04-10 | 2016-03-30 | Kyowa Hakko Kirin Co., Ltd. | Method for treatment of blood tumor using anti-tim-3 antibody |
US20140296218A1 (en) | 2012-10-25 | 2014-10-02 | Whitehead Institute For Biomedical Research | Super-enhancers and methods of use thereof |
CA2932120C (en) * | 2013-12-06 | 2023-09-19 | Celgene Corporation | Methods for determining drug efficacy for the treatment of diffuse large b-cell lymphoma, multiple myeloma, and myeloid cancers |
JP6367038B2 (ja) * | 2014-07-31 | 2018-08-01 | 学校法人近畿大学 | 受容体の細胞内輸送制御による白血病治療のための新規医薬組成物 |
JP2018512396A (ja) * | 2015-03-09 | 2018-05-17 | キングス・カレッジ・ロンドン | Th1応答を増強するためのrarアルファアゴニストを用いた併用療法 |
ES2898676T3 (es) * | 2015-11-25 | 2022-03-08 | Io Therapeutics Inc | Agonistas selectivos de rar-alfa resistentes a CYP26 en el tratamiento del cáncer |
-
2017
- 2017-04-07 IL IL262156A patent/IL262156B2/en unknown
- 2017-04-07 CN CN201780032969.9A patent/CN109310657B/zh active Active
- 2017-04-07 AU AU2017248187A patent/AU2017248187B2/en active Active
- 2017-04-07 CN CN202211503860.8A patent/CN115737821B/zh active Active
- 2017-04-07 EP EP17719772.0A patent/EP3452032A1/en active Pending
- 2017-04-07 MX MX2018012250A patent/MX2018012250A/es unknown
- 2017-04-07 KR KR1020227036152A patent/KR20220148926A/ko not_active Application Discontinuation
- 2017-04-07 KR KR1020187032334A patent/KR102457851B1/ko active IP Right Grant
- 2017-04-07 JP JP2018553078A patent/JP7034085B2/ja active Active
- 2017-04-07 CA CA3020173A patent/CA3020173A1/en active Pending
- 2017-04-07 IL IL307615A patent/IL307615A/en unknown
- 2017-04-07 WO PCT/US2017/026657 patent/WO2017177167A1/en active Application Filing
- 2017-04-07 BR BR112018070547-0A patent/BR112018070547A2/pt active Search and Examination
-
2021
- 2021-08-23 JP JP2021135461A patent/JP7284224B2/ja active Active
-
2023
- 2023-02-17 JP JP2023023318A patent/JP2023057151A/ja active Pending
- 2023-05-16 AU AU2023203040A patent/AU2023203040A1/en active Pending
- 2023-06-16 US US18/336,658 patent/US20240102106A1/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015101618A1 (en) | 2013-12-30 | 2015-07-09 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Combination of an arsenic compound and at least one retinoid for treating acute myeloid leukemia |
WO2016161107A1 (en) | 2015-03-31 | 2016-10-06 | Syros Pharmaceuticals, Inc. | METHODS OF STRATIFYING PATIENTS FOR TREATMENT WITH RETINOIC ACID RECEPTOR-α AGONISTS |
Also Published As
Publication number | Publication date |
---|---|
WO2017177167A1 (en) | 2017-10-12 |
AU2023203040A1 (en) | 2023-06-08 |
US20240102106A1 (en) | 2024-03-28 |
RU2018135302A (ru) | 2020-05-12 |
JP2019513758A (ja) | 2019-05-30 |
JP2023057151A (ja) | 2023-04-20 |
CN109310657A (zh) | 2019-02-05 |
RU2018135302A3 (ja) | 2020-11-06 |
KR102457851B1 (ko) | 2022-10-25 |
CA3020173A1 (en) | 2017-10-12 |
EP3452032A1 (en) | 2019-03-13 |
JP2021185171A (ja) | 2021-12-09 |
BR112018070547A2 (pt) | 2019-02-12 |
IL262156B2 (en) | 2024-03-01 |
AU2017248187B2 (en) | 2023-03-16 |
IL307615A (en) | 2023-12-01 |
CN109310657B (zh) | 2022-12-13 |
KR20180132841A (ko) | 2018-12-12 |
WO2017177167A4 (en) | 2017-12-21 |
CN115737821A (zh) | 2023-03-07 |
IL262156A (en) | 2018-11-29 |
AU2017248187A1 (en) | 2018-11-01 |
CN115737821B (zh) | 2024-04-12 |
MX2018012250A (es) | 2019-06-24 |
JP7284224B2 (ja) | 2023-05-30 |
IL262156B1 (en) | 2023-11-01 |
KR20220148926A (ko) | 2022-11-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20210285059A1 (en) | Methods of stratifying patients for treatment with retinoic acid receptor-alpha agonists | |
Sethuraman et al. | BHLHE40 confers a pro-survival and pro-metastatic phenotype to breast cancer cells by modulating HBEGF secretion | |
US20230042181A1 (en) | Methods of stratifying patients for treatment with retinoic acid receptor-alpha agonists | |
US20240102106A1 (en) | Methods of stratifying patients for treatment with retinoic acid receptor-alpha agonists | |
TW201805000A (zh) | 利用erk抑制劑之鱗狀細胞癌之治療 | |
WO2018067946A1 (en) | Methods of treating patients with a retinoic acid receptor-alpha agonist and an anti-cd38 antibody | |
Radujkovic et al. | Expression of CDKN1C in the bone marrow of patients with myelodysplastic syndrome and secondary acute myeloid leukemia is associated with poor survival after conventional chemotherapy | |
RU2799789C2 (ru) | Агонисты rara для лечения омл и мдс | |
JP2023500950A (ja) | マントル細胞リンパ腫(mcl)対象を特定するための鉄スコアおよびインビトロ方法ならびに治療的使用および方法 | |
KR20230087445A (ko) | Aml의 치료 요법 및 rara 작용제, 저메틸화제, 및 bcl-2 억제제의 용도 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20200407 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20210224 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210301 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20210526 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20210729 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210823 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20220105 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20220204 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20220301 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7034085 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |