CN118027014A - PROTAC chimeric body, preparation thereof and application thereof in preparation of targeted degradation RIPK3 drugs - Google Patents
PROTAC chimeric body, preparation thereof and application thereof in preparation of targeted degradation RIPK3 drugs Download PDFInfo
- Publication number
- CN118027014A CN118027014A CN202410168595.5A CN202410168595A CN118027014A CN 118027014 A CN118027014 A CN 118027014A CN 202410168595 A CN202410168595 A CN 202410168595A CN 118027014 A CN118027014 A CN 118027014A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- protac
- ripk3
- chimera
- 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.)
- Pending
Links
- 238000011865 proteolysis targeting chimera technique Methods 0.000 title claims abstract description 38
- 229940124823 proteolysis targeting chimeric molecule Drugs 0.000 title claims abstract description 38
- 108010026668 snake venom protein C activator Proteins 0.000 title claims abstract description 38
- 230000015556 catabolic process Effects 0.000 title claims abstract description 25
- 238000006731 degradation reaction Methods 0.000 title claims abstract description 25
- 239000003814 drug Substances 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 101001089266 Homo sapiens Receptor-interacting serine/threonine-protein kinase 3 Proteins 0.000 title claims description 39
- 102100033729 Receptor-interacting serine/threonine-protein kinase 3 Human genes 0.000 title claims description 39
- 229940079593 drug Drugs 0.000 title claims description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
- 101100034357 Arabidopsis thaliana RIPK gene Proteins 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 27
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 208000002223 abdominal aortic aneurysm Diseases 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 2
- 208000007474 aortic aneurysm Diseases 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical group OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 238000010931 ester hydrolysis Methods 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 230000002140 halogenating effect Effects 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 238000009396 hybridization Methods 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 230000010933 acylation Effects 0.000 claims 1
- 238000009472 formulation Methods 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 6
- 102000004169 proteins and genes Human genes 0.000 description 23
- 108090000623 proteins and genes Proteins 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000001962 electrophoresis Methods 0.000 description 6
- 150000003384 small molecules Chemical class 0.000 description 6
- 238000012546 transfer Methods 0.000 description 6
- 238000011534 incubation Methods 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000007865 diluting Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- ZCDBTQNFAPKACC-UHFFFAOYSA-N n-(6-propan-2-ylsulfonylquinolin-4-yl)-1,3-benzothiazol-5-amine Chemical compound C1=C2SC=NC2=CC(NC2=CC=NC3=CC=C(C=C32)S(=O)(=O)C(C)C)=C1 ZCDBTQNFAPKACC-UHFFFAOYSA-N 0.000 description 4
- 230000017074 necrotic cell death Effects 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000002033 PVDF binder Substances 0.000 description 3
- 239000006180 TBST buffer Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 3
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 125000005647 linker group Chemical group 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000001338 necrotic effect Effects 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 102000044159 Ubiquitin Human genes 0.000 description 2
- 108090000848 Ubiquitin Proteins 0.000 description 2
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 description 2
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000593 degrading effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- AGJSNMGHAVDLRQ-IWFBPKFRSA-N methyl (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-amino-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,3-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoate Chemical compound SC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(=O)OC)CC1=CC=C(O)C(C)=C1C AGJSNMGHAVDLRQ-IWFBPKFRSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000003032 molecular docking Methods 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000002531 positive electrospray ionisation time-of-flight mass spectrometry Methods 0.000 description 2
- 239000003531 protein hydrolysate Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000004088 simulation Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- -1 2-(4-(3-(4-(benzo[d]thiazol-5-ylamino)quinolin-6-yl)phenyl)piperazin-1-yl)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)acetamide Chemical compound 0.000 description 1
- HKEOVRSOFLWJAF-UHFFFAOYSA-N BrC(C=C12)=CC=C1N=CC=C2NC(C=C1)=CC2=C1SC=N2 Chemical compound BrC(C=C12)=CC=C1N=CC=C2NC(C=C1)=CC2=C1SC=N2 HKEOVRSOFLWJAF-UHFFFAOYSA-N 0.000 description 1
- 102000015367 CRBN Human genes 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
- 108010076667 Caspases Proteins 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 229940123621 Nedd 8 activating enzyme inhibitor Drugs 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 101710092490 Protein kinase 3 Proteins 0.000 description 1
- 101150025038 RIPK3 gene Proteins 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000021597 necroptosis Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 238000000751 protein extraction Methods 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 230000018883 protein targeting Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- MPUQHZXIXSTTDU-QXGSTGNESA-N sulfamic acid [(1S,2S,4R)-4-[4-[[(1S)-2,3-dihydro-1H-inden-1-yl]amino]-7-pyrrolo[2,3-d]pyrimidinyl]-2-hydroxycyclopentyl]methyl ester Chemical compound C1[C@H](O)[C@H](COS(=O)(=O)N)C[C@H]1N1C2=NC=NC(N[C@@H]3C4=CC=CC=C4CC3)=C2C=C1 MPUQHZXIXSTTDU-QXGSTGNESA-N 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of medicaments, in particular to PROTAC chimera which is a compound with a structure shown in a formula 1). The invention also includes the preparation and application of the compound. The invention provides a brand new compound which has excellent effect of targeted degradation of RIPK 3.
Description
Technical field:
The invention belongs to the technical field of drug synthesis, and particularly relates to the field of drug small molecule development.
The background technology is as follows:
programmed necrosis (Programmed necrosis), also known as necrotic apoptosis (Necroptosis), is a Caspase-independent mode of programmed cell death, unlike apoptosis. The programmed necrosis is characterized by receptor-interacting protein kinase3 (Receptor Interactingprotein kinase, RIPK 3) mediated phosphorylation of a mixed-series protein kinase-like domain (MLKL). Ripk3 is a key protein for necrotic apoptosis, and the mediated signal path is closely related to the inflammatory reaction of the organism, and can induce activation of inflammatory corpuscles and promote expression of inflammatory cytokines and amplify the inflammatory reaction by promoting cell necrosis and releasing DAMPs. Therefore, the RIPK3 is targeted and degraded, so that necrotic apoptosis of cells can be effectively inhibited, and a candidate medicine can be provided for treating diseases related to inflammation.
Protein targeted degradation chimera (Proteolysis-TARGETING CHIMERAS, PROTAC) is a heterobifunctional molecule, a technique first proposed by Sakamoto et al in 2001 and reported a peptide-based degradation agent. Later, researchers developed a variety of small molecules PROTAC that target degradation of different proteins on this basis and exhibited more excellent properties. Such compounds consist of E3 ubiquitin ligase ligand, linker and target protein ligand. PROTAC, acting as a ternary complex with the E3 ubiquitin ligase and the target protein, promotes ubiquitin tagging of the target protein by means of the ubiquitin proteinase system, and then undergoes proteasome degradation, after which PROTAC is released again for reuse. Because of its unique "event-driven pattern", PROTAC has several distinct advantages over conventional inhibitors for degradation of target proteins, including overcoming drug resistance, high selectivity, ability to act on "non-patentable proteins", high efficiency, low toxicity, etc. The PROTAC technology is applied to the development of new medicine molecules, so that the PROTAC molecules can become a new medicine with great prospect in the next generation.
The invention comprises the following steps:
In view of the above, the invention aims to provide PROTAC chimeric for targeted degradation of RIPK3, and a preparation method and application thereof.
PROTAC chimeric, which is a compound having the structure of formula 1;
In the formula 1, Y is a carbon chain or a heteroatom hybridization carbon chain, and the carbon chain is provided with a substituent group;
The carbon number of the carbon chain is between 6 and 12, the heteroatom is O or N, and the substituent comprises at least one of H, C 1～C6 alkyl, C 1～C6 alkoxy, aryl, ester group and amide group.
The invention provides PROTAC small molecules with a brand new structure shown in formula 1, wherein the small molecules shown in formula 1 can accidentally target and degrade RIPK3 protein, and can be used for treating related diseases.
Preferably, Y is- (CH 2) n-, wherein n is 8 to 12, more preferably 9 to 11; and still further 10.
For example, preferred PROTAC chimeras of the present invention are compounds having the structure of formula 1-A.
The research of the invention shows that the linking group of Y is further optimally controlled, which can unexpectedly further improve the intramolecular synergistic effect of the compound and further improve the targeted degradation capability of RIPK3 protein.
The invention also provides a preparation method of the PROTAC chimeric body, which is prepared by reacting a compound shown in a formula 2 with a compound shown in a formula 3;
in the formula 2, Y is as in the formula 1, and in the formula 3, R is-OH, halogen or alkoxy.
In the present invention, the formula 2: the reaction conditions of formula 3 are not particularly limited and can be controlled according to the conventional amidation reaction method, for example, formula 2: the molar ratio of the reaction of the formula 3 is 1-1.3:1.
When R in formula 3 is hydroxy, it is also preferable to add a hydroxy activator during the reaction.
Preferably, an acid binding agent is also allowed to be added during the reaction of formulas 2 and 3.
The temperature of the reaction process is not particularly limited and may be, for example, room temperature. The reaction time can be adjusted as desired, for example, by conventional means of a central control reaction.
In the present invention, the formula 2 is prepared by reacting the formula 4 with the formula 5, followed by deprotection:
y in the formula 5 is as in the formula 1, and R1 is a protecting group, and further is an alkoxycarbonyl group (for example, may be a-COOR a group, and R a is a C1-C6 alkyl group).
The reactions of formula 4 and formula 5 may be carried out by conventional substitution reaction means. For example, the molar ratio of formula 4 to formula 5 is 1:1 to 1.3. The acid binding agent is preferably added during the reaction. The temperature of the reaction process may be, for example, 50 to 100 ℃.
In the invention, the formula 3 is a formula 3-A, which is a compound of formula 3 in which R is-OH, and is obtained by reacting a compound of formula 6 with a compound of formula 7 and then performing an ester hydrolysis reaction.
In the formula 7, R 2 is C 1～C6 alkyl, X is halogen, and further Br.
In the reaction process of the formula 6 and the formula 7, the formula 6: the molar ratio of formula 7 is, for example, 1:1 to 1.3, the acid-binding agent is added during the reaction, and the temperature of the reaction process can be, for example, room temperature.
When formula 3 is formula 3-B, which is a compound of formula 3 wherein R is-halogen, it can be prepared by conventional acylation reaction of formula 3-a with a halogenating reagent.
When formula 3 is formula 3-C, which is a compound of formula 3 wherein R is an ester group, it can be prepared by conventional esterification of formula 3-A with an alcohol.
In the invention, the formula 6 is obtained by performing suzuki coupling reaction on the compounds of the formula 8 and the formula 9:
In the formula 8, X is halogen;
In formula 9, R3 is a borate group, and R4 is a conventional amino protecting group (for example, a-COOR a group and R a is a C1-C6 alkyl group).
In the present invention, the formulas 8 and 9 can be prepared by a conventional suzuki coupling reaction.
The invention also provides an application of the PROTAC chimeric body in preparing a targeted degradation RIPK3 drug.
The application of the invention, the targeted degradation RIPK3 drug is an anti-inflammatory drug, and can be further diseases such as abdominal aortic aneurysm or thermal jet diseases which realize pharmacological effects by degrading RIPK 3.
The application of the invention combines PROTAC chimeric and pharmaceutically acceptable auxiliary materials to prepare pharmaceutically acceptable preparations.
The invention also provides a targeted degradation RIPK3 drug, which comprises a pharmaceutically effective amount of PROTAC chimeric body.
The targeted degradation RIPK3 drug also comprises pharmaceutically acceptable auxiliary materials;
The targeted degradation RIPK3 drug provided by the invention also has a pharmaceutically acceptable dosage form.
Advantageous effects
The invention provides PROTAC small molecules with a brand new structure shown in formula 1, wherein the small molecules shown in formula 1 can accidentally target and degrade RIPK3 protein, and can be used for treating related diseases.
Drawings
FIG. 1 is a schematic and statistical diagram of the protein bands of the effect of compound XC-1 on intracellular RIPK3 protein content at different doses;
FIG. 2 is a schematic and statistical diagram of the protein bands of compound XC-1 and positive control (GSK 872) at different doses affecting intracellular RIPK3 protein content;
FIG. 3 is a schematic and statistical diagram of the protein bands of the effect of 20. Mu.M dose of compound XC-1 on the protein content of RIPK3 in cells after various pre-treatments;
FIG. 4 is a graph showing the results of a study of binding between different molecules and RIPK3 proteins in example 4;
Detailed Description
The following describes the present invention in detail with reference to examples.
A typical PROTAC chimeric of the invention, exemplified by formula 1-A, is synthesized by, for example:
the invention also discloses a preparation method of PROTAC chimeric body for targeted degradation of RIPK3 protein, which comprises the following steps:
The compound shown in the formulas II and III is dissolved in ethanol together according to the mol ratio of 1:1.2, a proper amount of 10M hydrochloric acid is added, reflux reaction is carried out for 2.5 hours at 82 ℃, and the hydrochloride form of the compound shown in the formula IV is obtained after filtration and drying;
The compound shown in the formula IV and the formula V are dissolved in a mixed solvent (dioxane: water=4:1) together according to the mol ratio of 1:1.2, 3 times equivalent of CsCO 3 and 0.05 equivalent of Pd (dppf) Cl 2 are added, the mixture is reacted for 12 hours at the temperature of 95 ℃ under the protection of N 2, after the reaction is finished, the compound shown in the formula VI is obtained through column chromatography purification, the compound is dissolved in dichloromethane, and a proper amount of 10M hydrochloric acid solution is added, so that the hydrochloride form of the compound shown in the formula VII is obtained.
The compound shown in the formula VII and the compound shown in the formula VIII are dissolved in DMF together according to the mol ratio of 1:1.2, 3 times of equivalent K 2CO3 is added, the reaction is carried out for 6 hours at the normal temperature of 25-30 ℃, after the reaction is finished, the compound shown in the formula IX is obtained through column chromatography purification, the compound is dissolved in dichloromethane, and a proper amount of 10M hydrochloric acid solution is added, so that the hydrochloride form of the compound shown in the formula X is obtained.
The compound shown in the formula XI and XII are dissolved in DMF together according to the mol ratio of 1:1.2, 2 times of equivalent DIPEA is added, the reaction is carried out for 6 hours at 80 ℃, after the reaction is finished, the compound shown in the formula XIII is obtained by column chromatography purification, the compound is dissolved in dichloromethane, and a proper amount of 10M hydrochloric acid solution is added, so that the hydrochloride form of the compound shown in the formula XIV is obtained.
The compound shown as the formula X and the formula XIV are dissolved in DMF together according to the mol ratio of 1:1.2, then 1.2 equivalent HOBT, 1.2 equivalent EDCI and 2 equivalent TEA are added for reaction for 12 hours at the normal temperature of 25-30 ℃ to obtain the compound I, namely XC-1;
the invention also discloses preparation of PROTAC chimeric XC-1 targeting RIPK3 and application thereof in degrading RIPK3 protein in cells.
The beneficial effects of the invention are as follows: based on RIPK3 inhibitor (GSK 872) reported in literature, the invention develops PROTAC chimeric body targeting RIPK3 with novel structure, and related experiments prove that the protein targeting degradation chimeric body can bind RIPK3 protein and cause effective degradation, thereby causing application of inhibiting tumor cell proliferation capacity. Thereby having excellent control effect on RIPK3 high expression related diseases.
Example 1: PROTAC chimeras for synthesis of targeted RIPK3
PROTAC chimeras targeting RIPK3 were synthesized using the following synthetic pathway:
synthesis of Compound IV:
And (3) taking the compounds II and III, dissolving the compounds II and III in a proper amount of ethanol solution according to a molar ratio of 1:1.2, adding a proper amount of 10M hydrochloric acid, carrying out reflux reaction at 82 ℃ for 2.5h, filtering the reaction solution, retaining a solid collection, and drying to obtain a hydrochloride form of the compound IV.
Synthesis of compound VII:
And (2) taking the compound IV and the compound V to be co-dissolved in a mixed solvent (dioxane: water=4:1) according to the molar ratio of 1:1, adding 3 times equivalent CsCO 3 and 0.05 equivalent Pd (dppf) Cl 2, reacting for 12 hours at the temperature of 95 ℃ under the protection of N 2, diluting with ethyl acetate, washing with water and saturated sodium chloride aqueous solution respectively for 3 times after the reaction is finished, drying with anhydrous sodium sulfate, filtering, rotationally evaporating the filtrate to dryness, obtaining a concentrate, separating the concentrate by silica gel column chromatography (eluent is petroleum ether/ethyl acetate with the volume ratio of 1:1), obtaining a collection, dissolving the collection in a small amount of dichloromethane solution, adding a proper amount of ethyl acetate hydrochloride solution, reacting for 0.5 hours at the temperature of 25-30 ℃, filtering and drying to obtain the hydrochloride form of the corresponding compound VII.
Synthesis of Compound X:
Taking the compound VII and VIII to be co-dissolved in DMF according to the mol ratio of 1:1.2, adding 3 times of equivalent K 2CO3, reacting for 6 hours at normal temperature of 25-30 ℃, diluting with ethyl acetate after the reaction is finished, washing with water and saturated sodium chloride aqueous solution respectively for 3 times, drying with anhydrous sodium sulfate, filtering, rotationally evaporating filtrate to dryness, obtaining a concentrate, separating the concentrate by silica gel column chromatography (the eluent is petroleum ether/ethyl acetate with the volume ratio of 1:1), obtaining a collection, dissolving the collection in a small amount of dichloromethane solution, adding a proper amount of ethyl acetate hydrochloride solution, reacting for 0.5 hours at the normal temperature of 25-30 ℃, filtering and drying to obtain the hydrochloride form of the corresponding compound X.
Synthesis of Compound XIV:
Taking the compound XI and XII to be co-dissolved in DMF according to the mol ratio of 1:1.2, adding 2 times equivalent of DIPEA, reacting for 6 hours at 80 ℃, diluting with ethyl acetate after the reaction is finished, washing with water and saturated sodium chloride aqueous solution for 3 times, drying with anhydrous sodium sulfate, filtering, rotationally evaporating filtrate to dryness, obtaining a concentrate, separating the concentrate by silica gel column chromatography (the eluent is petroleum ether/ethyl acetate with the volume ratio of 2:1), obtaining a collection, dissolving the collection in a small amount of dichloromethane solution, adding a proper amount of ethyl acetate hydrochloride solution, reacting for 0.5 hour at the normal temperature of 25-30 ℃, filtering and drying to obtain the hydrochloride form of the corresponding compound XIV.
Synthesis of Compound I:
And (3) taking the compound X and the XIV, dissolving the compound X and the XIV in DMF according to the molar ratio of 1:1.2, adding 1.2 equivalents of HOBT, 1.2 equivalents of EDCI and 2 equivalents of TEA, reacting for 12 hours at the normal temperature of 25-30 ℃, diluting with ethyl acetate after the reaction, washing with water and saturated sodium chloride aqueous solution for 3 times in sequence, drying with anhydrous sodium sulfate, filtering, rotationally evaporating the filtrate to dryness, and obtaining a concentrate, and separating by using a silica gel column chromatography (the eluent is methylene dichloride/methanol with the volume ratio of 20:1), thereby obtaining the compound I.
The partial structure characterization result of the synthesized compound is as follows:
N-(6-bromoquinolin-4-yl)benzo[d]thiazol-5-amine.(IV)
Yellow solid，yield：85％.
1H NMR(400MHz,DMSO-d6)δ11.34–11.24(m,1H),9.54(s,1H),9.21(dt,J＝7.0,2.3Hz,1H),8.54(d,J＝7.0Hz,1H),8.39(d,J＝8.5Hz,1H),8.22(t,J＝2.5Hz,1H),8.08(dd,J＝9.1,2.8Hz,1H),7.62(dd,J＝8.6,2.0Hz,1H),6.92(d,J＝7.0Hz,1H).
13C NMR(101MHz,DMSO-d6)δ158.91,154.87,154.41,143.55,137.68,137.18,135.92,133.19,126.69,124.46,123.55,122.89,120.44,120.09,119.10,101.07.
TOF MS ES+:355.9860[M+H]+,(calcd for C16H10N3BrS,355.9857).
2-(4-(3-(4-(benzo[d]thiazol-5-ylamino)quinolin-6-yl)phenyl)piperazin-1-yl)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)acetamide.(XC-1)
Yellow oil，yield：25％.
1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),9.32(s,1H),8.69(d,J＝1.9Hz,1H),8.49(d,J＝5.3Hz,1H),8.23(d,J＝8.6Hz,1H),8.06(dd,J＝8.7,2.0Hz,2H),7.97(d,J＝8.8Hz,1H),7.77(t,J＝6.0Hz,1H),7.63–7.49(m,3H),7.43–7.37(m,2H),7.33(d,J＝7.6Hz,1H),7.22(d,J＝22.6Hz,1H),7.03(d,J＝5.4Hz,2H),7.02–6.99(m,1H),6.48(q,J＝6.7,5.9Hz,1H),4.62–4.41(m,1H),3.48(s,2H),3.34–3.30(m,4H),3.28–3.20(m,2H),3.11(q,J＝6.7Hz,2H),2.99(s,2H),2.63(t,J＝4.8Hz,4H),2.33–2.27(m,2H),1.55(p,J＝7.1Hz,2H),1.43(p,J＝6.9Hz,2H),1.33–1.24(m,12H).
13C NMR(101MHz,DMSO-d6)δ173.02,170.47,169.29,157.80,154.65,152.06,151.12,148.74,148.46,146.66,141.10,139.74,137.64,136.30,133.05,130.01,129.19,129.01,123.55,121.94,120.28,120.09,118.49,117.03,116.59,115.15,114.65,110.52,102.23,61.77,53.30,52.04,51.68,48.70,38.64,30.97,29.41,26.82,24.07.
TOF MS ES+:906.4120[M+H]+,(calcd for C51H55O5N9S,906.4125).
example 2: RIPK3 degradation function verification of compound XC-1
1. Cell culture and plating
The experiment used an L929 cell line with a passage number of 10 to 20 and good conditions. Cells were seeded in six well plates at a density of 1x 10 5/m L (2 x 10 4/cm 2), each well serving as a drug intervention group, and when cells were grown to 70% density, the drug addition group replaced DMEM medium containing different concentrations of compound I; the control group was supplemented with DMEM medium containing an equivalent amount of DMSO.
2. Cellular protein extraction
After the drug is added, the cell protein is extracted after being incubated for 48 hours in a 5% CO 2 cell incubator at 37 ℃, and all the operations are carried out on an ice box, and the method specifically comprises the following steps:
① Preparing protein lysate: mixing with Western and IP cell lysates (bi yun tian, P0013) +1% pmsf (bi yun tian, ST 505);
② The medium was removed and the cells in the six well plates were rinsed once with 1ml PBS;
③ Adding 120 mu L of protein lysate into each well, and incubating for 30min in a refrigerator at 4 ℃;
④ Scraping off the adherent cells by using a cell scraper, and transferring the cells and lysate to a 1.5mL EP tube with a precooled bottom;
⑤ The EP tube with the cells collected was centrifuged at 13300r/min for 15min at 4 ℃;
⑥ After centrifugation, the supernatant was transferred to another bottom pre-chilled 1.5mL EP tube.
3. Sample preparation and Western Blot
The whole process of sample preparation and Western Blot specifically comprises the following steps:
① Total protein concentration determination: the total protein concentration determination was done using BCA colorimetric. 2 mu L of protein extract is added into a 96-well plate, PBS is diluted to 20 mu L, 200 mu L of BCA working solution is prepared and added, and absorbance at 562nm is measured after incubation for 30min at 37 ℃, and three replicates are performed for each sample well. A standard curve was drawn using protein standards provided in BCA kit (Thermo, 23225), and the average total protein concentration of each sample was calculated from the obtained absorbance values, and the total protein loading amounts were unified to calculate the loading volumes of each sample.
② Sample preparation: the protein sample was mixed with 5x Loading Buffer (Thermo, NP 0008) and the cell extract at a 1:4 volume ratio, and heated in a metal bath at 100℃for 10min.
③ Electrophoresis: the electrophoresis solution was prepared by adding purified water to a volume of 1L using 14.4g glycine 3.03g TRIS base,1g SDS. Protein samples or 2 mu L of protein markers are sequentially added into each well, a pre-prepared electrophoresis solution is filled into an electrophoresis tank, electrophoresis is performed for 30min at 80V voltage, and then electrophoresis is performed for 50min at 120V voltage.
④ Transferring: the transfer solution was prepared by adding pure water to a volume of 1L using 14.4g glycine and 3.03g TRIS base. A sandwich system was composed in Transfer Buffer (Tris-Glycine-SDS-ethanol) and transferred to a Transfer tank filled with pre-prepared Transfer solution, and transferred on ice for 95min at 270mA current to Transfer the Western blot on the gel onto PVDF membrane.
⑤ Closing and cutting films: the PVDF membrane after membrane transfer is immediately placed into an incubation box of 5% skimmed milk powder with the front face facing downwards, shaken for 1h at normal temperature, washed three times with TBST solution, and then cut out strips at corresponding positions according to the molecular weights of eEF2K and GAPDH.
⑥ Incubation resistance: the primary RIPK3 antibody was 1:1000 diluted anti-RIPK3 (CST, 34933S, 1:1000), the primary GAPDH antibody was 1:2000 diluted GAPDH (Servicebio, GB 11002), and incubated at 4℃for 15-18h, after which the primary antibody was rinsed three times with TBST to remove unbound residual antibody on the membrane.
⑦ Secondary antibody incubation: the secondary antibody was incubated at 1:5000 dilution of rabbit secondary antibody for 2h at ambient temperature, after which the secondary antibody was rinsed three times with TBST to remove unbound residual antibody on the membrane.
⑧ Strip exposure: 2mL of luminous solution (New Saimei, P10300) is prepared and evenly added on the surface of the PVDF film in a dropwise manner, and the imaging is carried out by adopting an automatic exposure mode, so as to obtain the corresponding protein strips.
4. Band analysis and statistics
Image processing and band abundance analysis were performed using Image Lab software and data summary statistics were performed using Graph Pad software. Independent replicates were performed for each set of results.
The specific results are shown in FIG. 1, in which the compound XC-1 has a concentration-dependent and time-dependent degradation of RIPK3 proteins in L929 cells at different concentration doses. And at different concentrations XC-1 degraded RIPK3 far better than the positive control group (GSK 872) (fig. 2). After pretreatment of L929 cells with NEDD8 activating enzyme inhibitor MLN4924, proteasome inhibitor MG132, RIPK3 ligand (GSK 872) or CRBN E3 ubiquitin ligase ligand Thalidomide for 4h, the degradation effect of XC-1 on RIPK3 proteins was significantly recovered relative to the non-interfered group after incubation with XC-1 at a concentration of 20. Mu.M for 36h (FIG. 3).
Example 3
The structural formula A was paired by Maestro 13.5 softwareAnd formula VII in a docking simulation with RIPK3 (PDB code:7MX 3) it was found that, as shown in FIG. 4A, structural formula A, when bound to RIPK3, had its structure completely incorporated into the active pocket of RIPK3, which has been a hindrance to the design of PROTAC. In fig. 4B, the sulfonic acid group in the structural formula a is replaced by the benzene ring group replaced by meta-piperazine, so that the structural formula VII is obtained, and it is found that, compared with the structural formula a, the structural formula VII can well expose the piperazine ring to the solvent region, so that the linker of PROTAC is connected, and meanwhile, the structural formula VII can form interaction force with more pocket amino acids. In fig. 4C, the docking simulation score also indicates that formula VII may have better binding capacity to RIPK3 than formula a. VII was therefore taken as the RIPK3 recognition end of PROTAC that subsequently targets RIPK3 degradation. /(I)
Claims (10)
1. PROTAC chimera is characterized by being a compound having the structure of formula 1;
In the formula 1, Y is a carbon chain or a heteroatom hybridization carbon chain, and the carbon chain is provided with a substituent group;
The carbon number of the carbon chain is between 6 and 12, the heteroatom is O or N, and the substituent comprises at least one of H, C 1～C6 alkyl, C 1～C6 alkoxy, aryl, ester group and amide group.
2. The PROTAC chimera according to claim 1, wherein Y is- (CH 2) n-, wherein n is 8 to 12, further preferably 9 to 11; and still further 10.
3. A method of preparing the PROTAC chimera according to claim 1 or 2, characterized in that it is prepared by reacting a compound of formula 2 with a compound of formula 3;
in the formula 2, Y is as in the formula 1, and in the formula 3, R is-OH, halogen or alkoxy.
4. A method of producing PROTAC chimeras according to claim 3 wherein said formula 2 is produced by reacting formulas 4 and 5 followed by deprotection:
y in the formula 5 is as shown in the formula 1, and R1 is a protecting group, and further is alkoxycarbonyl.
5. A method of producing a PROTAC chimera according to claim 3 wherein formula 3 is formula 3-a, which is a compound of formula 3 wherein R is-OH, by reacting a compound of formula 6 with a compound of formula 7 followed by an ester hydrolysis reaction:
In the formula 7, R 2 is C 1～C6 alkyl, X is halogen and further Br;
preferably, the formula 3 is formula 3-B, which is a compound of formula 3 wherein R is-halogen, which is obtainable by acylation of formula 3-a with a halogenating agent;
Preferably, the formula 3 is a compound of formula 3-C, which is a compound of formula 3 wherein R is an ester group, which is obtainable by esterification of formula 3-A with an alcohol.
6. The method of claim 5 wherein the compound of formula 6 is obtained by suzuki coupling between compounds of formulas 8 and 9:
in the formula 8, X is halogen, and further is Br;
in the formula 9, R3 is a borate group, and R4 is an amino protecting group.
7. Use of the PROTAC chimera of claim 1 or 2 in the preparation of a medicament for targeted degradation of RIPK 3.
8. The use of PROTAC chimera according to claim 7, wherein the targeted degradation RIPK3 drug is an anti-inflammatory drug, further useful as a drug for the treatment of abdominal aortic aneurysm and/or thermal jet disease.
9. The use of PROTAC chimera according to claim 7 or 8, wherein said PROTAC chimera is combined with pharmaceutically acceptable excipients to produce a pharmaceutically acceptable formulation.
10. A targeted degradation RIPK3 drug comprising a pharmaceutically effective amount of the PROTAC chimera of claim 1 or 2;
Preferably, the composition further comprises pharmaceutically acceptable auxiliary materials;
preferably, also has a pharmaceutically acceptable dosage form.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410168595.5A CN118027014A (en) | 2024-02-06 | 2024-02-06 | PROTAC chimeric body, preparation thereof and application thereof in preparation of targeted degradation RIPK3 drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410168595.5A CN118027014A (en) | 2024-02-06 | 2024-02-06 | PROTAC chimeric body, preparation thereof and application thereof in preparation of targeted degradation RIPK3 drugs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118027014A true CN118027014A (en) | 2024-05-14 |
Family
ID=90985359
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202410168595.5A Pending CN118027014A (en) | 2024-02-06 | 2024-02-06 | PROTAC chimeric body, preparation thereof and application thereof in preparation of targeted degradation RIPK3 drugs |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN118027014A (en) |
-
2024
- 2024-02-06 CN CN202410168595.5A patent/CN118027014A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2022021841A1 (en) | Novel coronavirus main protease inhibitor, and preparation method therefor and use thereof | |
| CN110092745B (en) | Compound containing aromatic ring and application thereof | |
| RU2316554C2 (en) | Derivatives of indoline used as protein kinase inhibitors | |
| IL233984A (en) | Tetrahydro-quinazolinone derivatives, their preparation and pharmaceutical compositions containing them | |
| CN111909108B (en) | Biphenyl compound and preparation method and medical application thereof | |
| JP5583698B2 (en) | Azaindole derivatives as inhibitors of protein kinases ABL and SRC | |
| KR100696139B1 (en) | Alkylcarbamoyl naphthalenyloxyoctenoylhydroxyamide derivatives having inhibitory activity against histone deacetylase and preparation thereof | |
| WO2020228635A1 (en) | Egfr kinase inhibitor and application thereof in preparing anti-cancer drug | |
| KR20220142500A (en) | Compound and its preparation method and its application in the preparation of anticancer drugs | |
| JP2021513530A (en) | Tetrahydroisoquinoline compounds, methods of their preparation, pharmaceutical compositions containing such compounds and their use. | |
| CN113387932B (en) | Bifunctional compound for inducing BRD4 protein degradation | |
| CN114276333B (en) | Dihydroquinoxaline bromodomain bivalent inhibitors | |
| AU2005335661A1 (en) | Novel 4-amino-thieno[3,2-C]pyridine-7-carboxylic acid amides | |
| CN108349975A (en) | 4H- pyrazolos [1,5- α] benzimidazoles compound crystal form and preparation method thereof and intermediate | |
| CN118027014A (en) | PROTAC chimeric body, preparation thereof and application thereof in preparation of targeted degradation RIPK3 drugs | |
| CN116514779A (en) | 2, 4-disubstituted-5-fluoropyrimidine derivative and preparation method and application thereof | |
| CN109641909A (en) | The mechanism target and its treatment use of rapamycin signal pathway inhibitor | |
| CN114292270B (en) | BTK inhibitor and preparation method and application thereof | |
| CN115466245A (en) | Hydroxamic acid derivative of pyrimidopyridine and preparation method and application thereof | |
| CN111747927B (en) | Compounds as immunomodulators and uses thereof | |
| CN115715285A (en) | Compounds as UBR box domain ligands | |
| CN113087709A (en) | Pyrrolopyrimidine derivatives, and preparation method and application thereof | |
| CN115340502B (en) | BCL-XL inhibitor and preparation method and application thereof | |
| CN111777626B (en) | Venetian-dihydroartemisinin split compound and preparation and application thereof | |
| CN115368277B (en) | Biphenyl compound containing hydroxamic acid structure and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination |