CN111035641B - Gzd824及其药学上可接受的盐在治疗疾病中的新应用 - Google Patents
Gzd824及其药学上可接受的盐在治疗疾病中的新应用 Download PDFInfo
- Publication number
- CN111035641B CN111035641B CN201811184991.8A CN201811184991A CN111035641B CN 111035641 B CN111035641 B CN 111035641B CN 201811184991 A CN201811184991 A CN 201811184991A CN 111035641 B CN111035641 B CN 111035641B
- Authority
- CN
- China
- Prior art keywords
- gzd824
- flt3
- pharmaceutically acceptable
- acceptable salts
- substituted
- 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
- 150000003839 salts Chemical class 0.000 title claims abstract description 23
- 201000010099 disease Diseases 0.000 title abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title abstract description 12
- TZKBVRDEOITLRB-UHFFFAOYSA-N 4-methyl-n-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-(1h-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]benzamide Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2C=C3C=NNC3=NC=2)=C1 TZKBVRDEOITLRB-UHFFFAOYSA-N 0.000 title abstract description 5
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims abstract description 44
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims abstract description 43
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims abstract description 24
- 230000004927 fusion Effects 0.000 claims abstract description 13
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims abstract description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 8
- 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 abstract description 8
- 229950001626 quizartinib Drugs 0.000 abstract description 7
- 230000014509 gene expression Effects 0.000 abstract description 3
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- LEVIGHXVOVROGW-UHFFFAOYSA-N methanesulfonic acid;4-methyl-n-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-(1h-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]benzamide Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2C=C3C=NNC3=NC=2)=C1 LEVIGHXVOVROGW-UHFFFAOYSA-N 0.000 description 39
- 210000004027 cell Anatomy 0.000 description 34
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 29
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 26
- 230000000694 effects Effects 0.000 description 14
- 230000035772 mutation Effects 0.000 description 12
- 108091008794 FGF receptors Proteins 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 8
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- 230000006907 apoptotic process Effects 0.000 description 6
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 description 5
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 5
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 230000019491 signal transduction Effects 0.000 description 5
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000022131 cell cycle Effects 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
- 108010003374 fms-Like Tyrosine Kinase 3 Proteins 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 102200039431 rs121913488 Human genes 0.000 description 3
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-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
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102000001712 STAT5 Transcription Factor Human genes 0.000 description 2
- 108010029477 STAT5 Transcription Factor Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000007783 downstream signaling Effects 0.000 description 2
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 2
- GYQYAJJFPNQOOW-UHFFFAOYSA-N gilteritinib Chemical compound N1=C(NC2CCOCC2)C(CC)=NC(C(N)=O)=C1NC(C=C1OC)=CC=C1N(CC1)CCC1N1CCN(C)CC1 GYQYAJJFPNQOOW-UHFFFAOYSA-N 0.000 description 2
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-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
- 102000000412 Annexin Human genes 0.000 description 1
- 108050008874 Annexin Proteins 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 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
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 1
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 1
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 1
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 1
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 1
- 102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 1
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 101150093908 PDGFRB gene Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 238000011579 SCID mouse model Methods 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- -1 and the like Chemical class 0.000 description 1
- 230000006909 anti-apoptosis Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000011841 epidemiological investigation Methods 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 229940125829 fibroblast growth factor receptor inhibitor Drugs 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229950006304 gilteritinib Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 238000011134 hematopoietic stem cell transplantation Methods 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 description 1
- 229950010895 midostaurin Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 208000017426 precursor B-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer 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
- A61K31/33—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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了GZD824及其药学上可接受的盐在治疗疾病中的新应用，即3‑((1H‑吡唑[3,4‑b]吡啶‑5‑取代)乙炔基)‑4‑甲基‑N‑(4‑((4‑甲基哌嗪‑1‑取代)甲基)‑3‑(三氟甲基)苯基)苯甲酰胺(GZD824)及其药学上可接受的盐在制备疾病中的新应用应用，该疾病为急性髓细胞性白血病。特别GZD824及其药学上可接受的盐对FLT3‑ITD融合表达和/或FGFR1OP2‑FGFR1融合表达的或Quizartinib耐药的急性髓细胞性白血病具有很好的治疗作用。
Description
技术领域
本发明属于医药生物领域，涉及GZD824及其药学上可接受的盐在治疗疾病中的新应用，具体是涉及3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺(即GZD824)及其药学上可接受的盐的在治疗疾病中的新的应用。
背景技术
急性髓细胞性白血病(Acute myeloid leukemia，AML)是髓系造血干细胞恶性疾病。2016年美国有新增AML病人19,950个，死亡人数高达10,430人，占到白血病死亡人数的一半。我国流行病学调查显示，年轻人中患病率为2-3/10万，70岁以上患病率为13-15/10万(中国细胞生物学学报，2015，37(2)：299-308)。
FLT3(Fms-like tyrosine kinase 3，也叫Flk2)即FMS样酪氨酸激酶3，属于PDGFR(the platelet growth factor receptor)家族一员，属于III型受体酪氨酸激酶。FLT3在血液干细胞的增值和分化等方面起着重要的调节作用。在急性髓细胞白血病(AML)中，发现FLT3的活化突变或者过度表达(Heinrich Mini-Reviews in Medicinal Chemistry(2004)4(3):255-271,Kiyoi et al.Int J Hemato(2005)82:85-92)。
正常生理状态下，FLT3(FMS-like tyrosine kinase 3)与其配体FL结合后二聚化，进而活化下游信号蛋白如AKT，MAPK等，在造血细胞等增殖、分化中发挥重要作用。Nakao等研究人发现在高达30％的急性髓细胞性白血病患者中存在FLT3-ITD突变，随后Yamamoto等人于发现约有7％的急性髓细胞性白血病患者存在FLT3-TKD激活突变(以D835Y最常见)。FLT3突变引起非配体依赖下游信号通路持续激活，进而促进细胞的恶性增殖和抗凋亡等导致AML的发生(Stem Cell Investig.2017,4:48；.Int J Hematol.2013,97(6):683-94)。
FLT3-ITD突变能够作为AML患者预后判断的独立指标。在儿童AML患者中，发现16.5％的患者带有FLT3-ITD突变，治疗后的缓解率只有40％，并且8年无事件生存率(EFS)仅为7％；而非FLT3-ITD的突变的患者得缓解率高达70％，8年无事件生存率(EFS)为44％。同样成人患者中高达27％的患者是ITD阳性突变，其无病生存期(DFS)、EFS、总体存活率(OS)均较非突变患者低(Blood,2001,98:1752-1759；Blood,2008,11l(10).4930-4933)。
2017年，第一个一代FLT3抑制剂Midostaurin(PKC412，诺华制药)被FDA批准上市，其他非选择性的一代FLT3抑制剂还有Lestaurtinib、Sunitinb、Sorafetinib等。二代选择性FLT3抑制剂Quizartinib(AC-220)、Gilteritinib(ASP2215)正处于临床研究阶段，用于治疗FLT3-ITD突变阳性急性髓细胞性白血病及经一线治疗(合并造血干细胞移植HSCT)后病情复发或难治性AML患者的治疗。(Cells.2018,7(1).pii:E4；Am J Hematol.2018,93(2):213-221；Journal of Medicinal Chemistry,2018,61(9):3855-3869.)。
此外，FGFR1OP2-FGFR1融合表达也被证实与AML的发病、预后、治疗密切相关，FGFR抑制剂能够有效抑制FGFR1OP2-FGFR1的AML细胞的增殖(Haematologica.2016,101(3):e91-4；Haematologica.2013,98(1):103-6.)。
3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺(化学结构式
本发明代称为GZD824)是一类l三代小分子Bcr-Ab抑制剂，可以有效治疗慢性粒细胞白血病，尤其是对伊马替尼耐药的白血病患者具有较好的治疗效果(J Med Chem.2013,56(3):879-94)，以及可以治疗前体B细胞急性淋巴细胞白血病。
但是，3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺(代称为GZD824)能否对急性髓细胞性白血病具有很好的疗效作用，目前并不清楚。
发明内容
基于此，本发明的目的之一提供一种GZD824及其药学上可接受的盐在治疗疾病中的新应用，即3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺(代称为GZD824)及其药学上可接受的盐的在治疗疾病中的新的应用。
实现上述目的的技术方案如下。
3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺及其药学上可接受的盐在制备治疗急性髓细胞性白血病的药物中的应用。
3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺及其药学上可接受的盐在制备治疗FLT3-ITD融合表达的急性髓细胞性白血病的药物中的应用。
3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺及其药学上可接受的盐在制备治疗FGFR1OP2-FGFR1融合表达的急性髓细胞性白血病的药物中的应用。
3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺及其药学上可接受的盐在制备治疗FLT3-ITD融合表达和FGFR1OP2-FGFR1融合表达的急性髓细胞性白血病的药物中的应用。
3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺及其药学上可接受的盐在制备治疗Quizartinib耐药的急性髓细胞性白血病的药物中的应用。
本发明经过发明人的长期实验，创造性发现GZD824可以用于治疗急性髓性白血病，特别是通过靶向FLT3及FGFR蛋白激酶，应用于治疗FLT3和/或FGFR1异常的急性髓细胞性白血病以及Quizartinib耐药的急性髓细胞性白血病，将具有很好的疗效。
附图说明
图1是GZD824对二代FLT3抑制剂耐药细胞MV4-11-QR的抗增殖活性的结果示意图。
图2是GZD824对AML细胞FLT3及FGFR1信号通路的影响的结果示意图。
图3是GZD824对MV4-11细胞周期和凋亡的影响的结果示意图。
图4是GZD824对MV4-11体内移植瘤生长的抑制作用的结果示意图。
具体实施方式
为了便于理解本发明，下面将对本发明进行更全面的描述。本发明可以以许多不同的形式来实现，并不限于本文所描述的实施例。相反地，提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。实施例中所用到的各种常用化学试剂，均为市售产品。
除非另有定义，本发明所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不用于限制本发明。本发明所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
经过本发明的发明人的反复实验发现，GZD824具有FLT3及FGFR激酶抑制活性，体外有效抑制FLT3-ITD突变及FGFR1OP2-FGFR1突变的AML细胞增殖，并阻断AML细胞FLT3及FGFR信号通路，诱导AML细胞G0/G1周期阻滞和凋亡的作用；体内研究发现GZD824能够有效抑制AML细胞移植瘤的生长，具有较好的抗肿瘤作用。
本发明化合物的药学上可接受的盐包括通过本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如，常规的无毒盐包括无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐，也包括有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2一乙酰氧基一苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。Berg等，"Pharmaceutical Salts,"J.Pharm,Sci.'1977:66:1—19更详细描述了上文所述药学上可接受的盐及其它典型的药学上可接受的盐的制备。
3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺，以下简称GZD824，其按照现有方法进行合成得到或者购买。
实施例1 GZD824对FLT3及FGFR1等激酶的抑制活性
利用已经建立的基于FRET(荧光共振能量转移)的体外激酶筛选方法(J MedChem.2013,56(3):879-94)，研究GZD824及其对照药物Quizartinib对FLT3、FGFR1、等激酶的体外抑制活性，使用GrapPad5.0计算其半数抑制浓度(IC50)。
结果显示，GZD824具有FLT3及FGFR抑制活性，其FLT3及FGFR的活性分别为1.33±0.074、4.14±0.96nM，其中FLT3活性与选择性FLT3抑制剂Quizartinib相当。并且GZD824对FLT3-D835Y突变激酶的活性为223.8±55.6nM，而Quizartinib的活性为6486±1669nM。这说明GZD828可以对二代FLT3抑制剂Quizartinib的耐药突变有一定作用。
具体数据见表1。
表.1化合物的激酶抑制剂活性
| AV±SD(nM) | FLT3-WT | FLT3-D835Y | FGFR1 | FGFR2 | FGFR3 | FGFR4 |
| GZD824 | 1.33±0.074 | 223.8±55.6 | 4.14±0.96 | 2.77±0.082 | 8.10±0.15 | 30.27±21.66 |
| Quizartinib | 5.95±1.89 | 6486±1669 | >10000 | >10000 | >10000 | >10000 |
| Gilteritinib | 13.32±0.13 | 3.71±1.36 | >1000 | >1000 | >1000 | >1000 |
实施例2 GZD824对AML细胞的增殖抑制活性
本实验使用的细胞MV4-11(FLT3-ITD融合表达的急性髓细胞性白血病细胞系)、KG1(FGFR1OP2-FGFR1融合表达的急性髓细胞性白血病细胞系)及HL60、NB4(FLT3及FGFR野生型白血病细胞系)等白血病细胞系，均来自ATCC或者中国科学院典型培养物保藏委员会细胞库。MV4-11-QR细胞是由我们实验室使用二代FLT3抑制剂Quizartinib诱导MV4-11细胞获得的Quizartinib耐药细胞。3000-10000个上述细胞接种到96孔板中，然后加入不同浓度的GZD824(0-3μM)连续处理72小时。然后加入CCK8试剂，继续孵育1-3小时，接着用超级酶标仪测定其在450nm及650nm的吸光值。使用GrapPad5.0计算其半数抑制浓度(IC50)。
具体数据见表2和图1。
表2化合物对白血病细胞的增殖抑制活性
实施例3 GZD824对AML细胞FLT3信号通路的影响
蛋白质免疫印迹法研究GZD824对AML细胞信号通路的影响。将合适细胞浓度(1-2X106个/孔)的MV4-11FLT3-ITD或者HL60FLT3-WT等细胞接种到6孔板，用不同浓度的GZD824(0、0.8、4、20、100、500nM)处理细胞6小时，用SDS裂解液(CST推荐)裂解并抽提蛋白。进行SDS-PAGE电泳，转膜，一抗过夜，二抗室温2小时，然后使用ECL试剂盒显影。FLT3(3462)、pFLT3(3664)AKT(#4685S)、pAKT(#13038,#4060)、ERK1/2(#4695)、pERK1/2(#4370)、STAT5(9363)、pSTAT5(9359)等抗体购买自CST(Boston,MA,USA)，二抗购买自life公司。
结果表明GZD824在4nM水平即可抑制MV4-11细胞中FLT3及其下游信号通路蛋白如STAT5、ERK、AKT的活化，并且表现出良好的剂量依赖性。具体结果见图2。
实施例4 GZD824对AML细胞FGFR信号通路的影响
蛋白质免疫印迹法研究GZD824对AML细胞信号通路的影响。将合适细胞浓度(1-2X106个/孔)的KG1FGFR1OP2-FGFR1或者HL60FGFR-WT等细胞接种到6孔板，用不同浓度的GZD824(0、0.8、4、20、100、500nM)处理细胞6小时，用SDS裂解液(CST推荐)裂解并抽提蛋白。进行SDS-PAGE电泳，转膜，一抗过夜，二抗室温2小时，然后使用ECL试剂盒显影。FGFR、FRS、FLCγ及其磷酸化抗体购买自CST，二抗购买自life公司。
结果表明GZD824在20nM水平即可抑制KG1细胞中FGFR及其下游信号通路的活化，并且表现出良好的剂量依赖性。具体结果见图2。
实施例5 GZD824诱导AML细胞周期阻滞
不同浓度的GZD824(0、4、20、100nM)处理MV4-11细胞，分别于24、48小时后，按照细胞周期试剂盒步骤处理后，用流式细胞仪检测细胞周期。结果发现，GZD824可剂量依赖性和时间依赖性的诱导MV4-11细胞G0/G1阻滞。结果参见图3。
实施例6 GZD824诱导AML细胞凋亡
不同浓度的GZD824(0、4、20、100nM)处理MV4-11细胞，分别于24、48小时后，按照凋亡试剂盒(ANNEXIN V,PI)检测细胞凋亡。结果发现，GZD824可剂量依赖性和时间依赖性的诱导MV4-11细胞发生凋亡。结果见图3。
实施例7 GZD824体内抑制AML移植瘤的生长
将5X106个MV4-11FLT3-ITD细胞悬液(Matrigel：培养基，1:1)接种到SCID小鼠右前腋部皮下，待瘤体积长到100-200mm3时分组给药，以瘤体积曲线、瘤重等为指标，研究GZD824体内抗肿瘤作用。
结果发现GZD824在20mg/kg，po，q2d条件下基本可以完全消除MV4-11移植瘤的生长(图4)，并且没有产生明显的肝肾毒性(表.3)。
表.3 GZD824对MV4-11移植瘤模型动物肝肾生化功能的影响
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (1)
1.3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺及其药学上可接受的盐在制备治疗急性髓细胞性白血病的药物中的应用；
所述急性髓细胞性白血病为FLT3-ITD融合表达的急性髓细胞性白血病、FGFR1OP2-FGFR1融合表达的急性髓细胞性白血病或者FLT3-ITD融合表达和FGFR1OP2-FGFR1融合表达的急性髓细胞性白血病。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811184991.8A CN111035641B (zh) | 2018-10-11 | 2018-10-11 | Gzd824及其药学上可接受的盐在治疗疾病中的新应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811184991.8A CN111035641B (zh) | 2018-10-11 | 2018-10-11 | Gzd824及其药学上可接受的盐在治疗疾病中的新应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111035641A CN111035641A (zh) | 2020-04-21 |
| CN111035641B true CN111035641B (zh) | 2022-04-12 |
Family
ID=70229244
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811184991.8A Active CN111035641B (zh) | 2018-10-11 | 2018-10-11 | Gzd824及其药学上可接受的盐在治疗疾病中的新应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111035641B (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112237579B (zh) * | 2019-07-19 | 2022-03-29 | 苏州亚盛药业有限公司 | 药物组合及其用途 |
| CN114164248A (zh) * | 2020-09-11 | 2022-03-11 | 广州再极医药科技有限公司 | 一种fgfr抑制剂的筛选方法 |
| CN114533879B (zh) * | 2020-11-19 | 2023-09-29 | 广州顺健生物医药科技有限公司 | 治疗癌症的联合疗法 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101885722B (zh) * | 2010-07-01 | 2013-07-24 | 中国科学院广州生物医药与健康研究院 | 杂环炔苯类化合物及其药用组合物和应用 |
| CN106580993B (zh) * | 2016-07-25 | 2018-11-30 | 广州顺健生物医药科技有限公司 | 耐克替尼及其药学上可接受的盐在治疗疾病中的新的应用 |
-
2018
- 2018-10-11 CN CN201811184991.8A patent/CN111035641B/zh active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN111035641A (zh) | 2020-04-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Loh et al. | A phase 1 dosing study of ruxolitinib in children with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms: A Children's Oncology Group phase 1 consortium study (ADVL1011) | |
| CN111035641B (zh) | Gzd824及其药学上可接受的盐在治疗疾病中的新应用 | |
| Alvarado et al. | The PIM kinases in hematological cancers | |
| D’Cruz et al. | Novel Bruton’s tyrosine kinase inhibitors currently in development | |
| JP6724240B2 (ja) | 疾患の処置におけるネクチニブおよびその薬学的に許容可能な塩の新規な使用 | |
| US20200101077A1 (en) | Combination therapy | |
| KR20210102192A (ko) | 골수증식성 장애를 치료하는 방법 | |
| CN105050623A (zh) | Pi3k抑制剂和c-met抑制剂的组合 | |
| Xie et al. | Anwulignan is a novel JAK1 inhibitor that suppresses non‐small cell lung cancer growth | |
| JP2010534219A (ja) | Ｅｇｆｒ依存性疾患またはｅｇｆｒファミリーメンバーを標的とする薬剤に対して耐性を獲得した疾患の処置のための、イミダゾキノリンの使用 | |
| JP6526789B2 (ja) | 組み合わせ療法 | |
| JP2009537626A (ja) | ９−ヒドロキシエリプチシン誘導体による悪性表現型の復帰変異 | |
| CN110393718A (zh) | 阿托帕沙溴酸作为新型jak-stat3信号通路抑制剂的用途和研究方法 | |
| CN109602752B (zh) | 雷公藤甲素在诱导癌细胞自噬以及协同hdac抑制剂治疗肿瘤中的应用 | |
| CN111346092A (zh) | 安罗替尼在制备治疗急性髓系白血病药物的新用途 | |
| JP2015512416A (ja) | 神経芽細胞腫、ユーイング肉腫または横紋筋肉腫の治療に使用するための化合物 | |
| US20220354874A1 (en) | Therapeutic compositions and methods for treating cancers | |
| CN114469950A (zh) | 白屈菜碱在制备flt3-itd突变的急性髓系白血病治疗药物中的应用 | |
| TW200827361A (en) | Antitumor pharmaceutical composition | |
| KR20240073112A (ko) | PI3Ka 억제제와 KRAS G12D 억제제의 조합 및 관련된 치료 방법 | |
| CN112121052A (zh) | 丙烯酰基苯并氮杂*类化合物在制备防治血液肿瘤药物中的用途 | |
| Pinto | Anaplastic Thyroid Cancer: Identification of Candidate Therapeutics and Mechanisms of Disease Progression | |
| CN110420330A (zh) | 一种pi3k与mth1靶向药组合物及其应用 | |
| KR20230004455A (ko) | 멀티 키나제 억제제의 새로운 용도 | |
| Weaver | Venclexta Combination Treatment for Chronic Lymphocytic Leukemia |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |