WO2023051606A1 - Shp2抑制剂联合egfr-tki治疗和预防肿瘤疾病的医药用途 - Google Patents
Shp2抑制剂联合egfr-tki治疗和预防肿瘤疾病的医药用途 Download PDFInfo
- Publication number
- WO2023051606A1 WO2023051606A1 PCT/CN2022/122104 CN2022122104W WO2023051606A1 WO 2023051606 A1 WO2023051606 A1 WO 2023051606A1 CN 2022122104 W CN2022122104 W CN 2022122104W WO 2023051606 A1 WO2023051606 A1 WO 2023051606A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- day
- once
- egfr
- cancer
- tumor
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 110
- 229940121647 egfr inhibitor Drugs 0.000 title claims abstract description 63
- 239000003112 inhibitor Substances 0.000 title claims abstract description 49
- 238000011282 treatment Methods 0.000 title claims abstract description 27
- 230000002265 prevention Effects 0.000 title claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 67
- 229940079593 drug Drugs 0.000 claims abstract description 64
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 claims abstract description 50
- 101710116241 Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 claims abstract description 49
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 208000020816 lung neoplasm Diseases 0.000 claims description 33
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 31
- 201000005202 lung cancer Diseases 0.000 claims description 31
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 25
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 25
- -1 HLX-07 Chemical compound 0.000 claims description 24
- 230000035772 mutation Effects 0.000 claims description 22
- 206010059866 Drug resistance Diseases 0.000 claims description 21
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims description 18
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims description 17
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims description 17
- 229960003278 osimertinib Drugs 0.000 claims description 15
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical compound COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 claims description 15
- LPFWVDIFUFFKJU-UHFFFAOYSA-N 1-[4-[4-(3,4-dichloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]prop-2-en-1-one Chemical compound C=12C=C(OC3CCN(CC3)C(=O)C=C)C(OC)=CC2=NC=NC=1NC1=CC=C(Cl)C(Cl)=C1F LPFWVDIFUFFKJU-UHFFFAOYSA-N 0.000 claims description 14
- 229950009876 poziotinib Drugs 0.000 claims description 14
- 229950003046 tesevatinib Drugs 0.000 claims description 14
- HVXKQKFEHMGHSL-QKDCVEJESA-N tesevatinib Chemical compound N1=CN=C2C=C(OC[C@@H]3C[C@@H]4CN(C)C[C@@H]4C3)C(OC)=CC2=C1NC1=CC=C(Cl)C(Cl)=C1F HVXKQKFEHMGHSL-QKDCVEJESA-N 0.000 claims description 14
- BXTJCSYMGFJEID-XMTADJHZSA-N (2s)-2-[[(2r,3r)-3-[(2s)-1-[(3r,4s,5s)-4-[[(2s)-2-[[(2s)-2-[6-[3-[(2r)-2-amino-2-carboxyethyl]sulfanyl-2,5-dioxopyrrolidin-1-yl]hexanoyl-methylamino]-3-methylbutanoyl]amino]-3-methylbutanoyl]-methylamino]-3-methoxy-5-methylheptanoyl]pyrrolidin-2-yl]-3-met Chemical compound C([C@H](NC(=O)[C@H](C)[C@@H](OC)[C@@H]1CCCN1C(=O)C[C@H]([C@H]([C@@H](C)CC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)CCCCCN1C(C(SC[C@H](N)C(O)=O)CC1=O)=O)C(C)C)OC)C(O)=O)C1=CC=CC=C1 BXTJCSYMGFJEID-XMTADJHZSA-N 0.000 claims description 11
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 claims description 11
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 claims description 10
- 229950000908 nazartinib Drugs 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 239000005411 L01XE02 - Gefitinib Substances 0.000 claims description 9
- 239000005551 L01XE03 - Erlotinib Substances 0.000 claims description 9
- 229960001433 erlotinib Drugs 0.000 claims description 9
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims description 9
- 229960002584 gefitinib Drugs 0.000 claims description 9
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 claims description 9
- QQLKULDARVNMAL-UHFFFAOYSA-N icotinib Chemical compound C#CC1=CC=CC(NC=2C3=CC=4OCCOCCOCCOC=4C=C3N=CN=2)=C1 QQLKULDARVNMAL-UHFFFAOYSA-N 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 102200048955 rs121434569 Human genes 0.000 claims description 9
- 229960001686 afatinib Drugs 0.000 claims description 8
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 claims description 8
- 229950007440 icotinib Drugs 0.000 claims description 8
- FDMQDKQUTRLUBU-UHFFFAOYSA-N n-[3-[2-[4-(4-methylpiperazin-1-yl)anilino]thieno[3,2-d]pyrimidin-4-yl]oxyphenyl]prop-2-enamide Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC(OC=2C=C(NC(=O)C=C)C=CC=2)=C(SC=C2)C2=N1 FDMQDKQUTRLUBU-UHFFFAOYSA-N 0.000 claims description 8
- 229950000778 olmutinib Drugs 0.000 claims description 8
- FSXCKIBROURMFT-VGSWGCGISA-N (3ar,6ar)-n-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]-1-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carboxamide Chemical compound C=12C=C(NC(=O)N3C[C@@H]4N(C)CC[C@@H]4C3)C(OC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 FSXCKIBROURMFT-VGSWGCGISA-N 0.000 claims description 7
- UWXSAYUXVSFDBQ-CYBMUJFWSA-N 4-n-[3-chloro-4-(1,3-thiazol-2-ylmethoxy)phenyl]-6-n-[(4r)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]quinazoline-4,6-diamine Chemical compound C[C@@H]1COC(NC=2C=C3C(NC=4C=C(Cl)C(OCC=5SC=CN=5)=CC=4)=NC=NC3=CC=2)=N1 UWXSAYUXVSFDBQ-CYBMUJFWSA-N 0.000 claims description 7
- HISXHQFAOANCJX-UHFFFAOYSA-N butanedioic acid 4-ethyl-N-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]piperazine-1-carboxamide Chemical compound OC(=O)CCC(O)=O.CCN1CCN(CC1)C(=O)Nc1cc2c(Nc3cccc(c3)C#C)ncnc2cc1OC HISXHQFAOANCJX-UHFFFAOYSA-N 0.000 claims description 7
- OXWUWXCJDBRCCG-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-6-[2-(5,8-dioxa-10-azadispiro[2.0.4^{4}.3^{3}]undecan-10-yl)ethoxy]-7-methoxyquinazolin-4-amine Chemical compound C=12C=C(OCCN3CC4(C5(CC5)C3)OCCO4)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 OXWUWXCJDBRCCG-UHFFFAOYSA-N 0.000 claims description 7
- JYIUNVOCEFIUIU-GHMZBOCLSA-N n-[(3r,4r)-4-fluoro-1-[6-[(3-methoxy-1-methylpyrazol-4-yl)amino]-9-methylpurin-2-yl]pyrrolidin-3-yl]prop-2-enamide Chemical compound COC1=NN(C)C=C1NC1=NC(N2C[C@H]([C@H](F)C2)NC(=O)C=C)=NC2=C1N=CN2C JYIUNVOCEFIUIU-GHMZBOCLSA-N 0.000 claims description 7
- ZMUKJEHWLJBODV-UHFFFAOYSA-N n-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]prop-2-enamide;4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.FC1=CC=CC(COC=2C(=CC(NC=3C4=CC(NC(=O)C=C)=CC=C4N=CN=3)=CC=2)Cl)=C1 ZMUKJEHWLJBODV-UHFFFAOYSA-N 0.000 claims description 7
- 102200048928 rs121434568 Human genes 0.000 claims description 7
- WAKIMVYUBWMMHJ-FXRZFVDSSA-N tarloxotinib bromide Chemical compound [Br-].CN1C=NC([N+]([O-])=O)=C1C[N+](C)(C)C\C=C\C(=O)NC(N=CC1=NC=N2)=CC1=C2NC1=CC=C(Cl)C(Br)=C1 WAKIMVYUBWMMHJ-FXRZFVDSSA-N 0.000 claims description 7
- SADXACCFNXBCFY-IYNHSRRRSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl]-3-[(2r)-1-methylpyrrolidin-2-yl]prop-2-enamide Chemical compound C=12C=C(NC(=O)\C=C\[C@@H]3N(CCC3)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 SADXACCFNXBCFY-IYNHSRRRSA-N 0.000 claims description 6
- XCZIYUDQUDWQHI-UHFFFAOYSA-N 1-[3-(6,7-dimethoxyquinazolin-4-yl)oxyphenyl]-3-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]urea;hydrochloride Chemical compound Cl.C=12C=C(OC)C(OC)=CC2=NC=NC=1OC(C=1)=CC=CC=1NC(=O)NC=1C=C(C(C)(C)C(F)(F)F)ON=1 XCZIYUDQUDWQHI-UHFFFAOYSA-N 0.000 claims description 6
- WSOHOUHPUOAXIN-UHFFFAOYSA-N 2-n-[4-(4-methylpiperazin-1-yl)phenyl]-9-propan-2-yl-8-n-pyridin-3-ylpurine-2,8-diamine Chemical compound N=1C2=CN=C(NC=3C=CC(=CC=3)N3CCN(C)CC3)N=C2N(C(C)C)C=1NC1=CC=CN=C1 WSOHOUHPUOAXIN-UHFFFAOYSA-N 0.000 claims description 6
- AILRADAXUVEEIR-UHFFFAOYSA-N 5-chloro-4-n-(2-dimethylphosphorylphenyl)-2-n-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine Chemical compound COC1=CC(N2CCC(CC2)N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1P(C)(C)=O AILRADAXUVEEIR-UHFFFAOYSA-N 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- GHKOONMJXNWOIW-UHFFFAOYSA-N CN(CCN(C1=NC(=C(C=C1NC(C=C)=O)NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C)OCC(F)(F)F)C)C Chemical compound CN(CCN(C1=NC(=C(C=C1NC(C=C)=O)NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C)OCC(F)(F)F)C)C GHKOONMJXNWOIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002136 L01XE07 - Lapatinib Substances 0.000 claims description 6
- RRMJMHOQSALEJJ-UHFFFAOYSA-N N-[5-[[4-[4-[(dimethylamino)methyl]-3-phenylpyrazol-1-yl]pyrimidin-2-yl]amino]-4-methoxy-2-morpholin-4-ylphenyl]prop-2-enamide Chemical compound CN(C)CC=1C(=NN(C=1)C1=NC(=NC=C1)NC=1C(=CC(=C(C=1)NC(C=C)=O)N1CCOCC1)OC)C1=CC=CC=C1 RRMJMHOQSALEJJ-UHFFFAOYSA-N 0.000 claims description 6
- 108010086229 SYN-004 Proteins 0.000 claims description 6
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 6
- MXDSJQHFFDGFDK-CYBMUJFWSA-N [4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl] (2r)-2,4-dimethylpiperazine-1-carboxylate Chemical compound C=12C=C(OC(=O)N3[C@@H](CN(C)CC3)C)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F MXDSJQHFFDGFDK-CYBMUJFWSA-N 0.000 claims description 6
- 229940008421 amivantamab Drugs 0.000 claims description 6
- 229950004272 brigatinib Drugs 0.000 claims description 6
- 229950002205 dacomitinib Drugs 0.000 claims description 6
- LVXJQMNHJWSHET-AATRIKPKSA-N dacomitinib Chemical compound C=12C=C(NC(=O)\C=C\CN3CCCCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 LVXJQMNHJWSHET-AATRIKPKSA-N 0.000 claims description 6
- 206010017758 gastric cancer Diseases 0.000 claims description 6
- 229960004891 lapatinib Drugs 0.000 claims description 6
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 claims description 6
- 208000032839 leukemia Diseases 0.000 claims description 6
- 201000007270 liver cancer Diseases 0.000 claims description 6
- 208000014018 liver neoplasm Diseases 0.000 claims description 6
- 229940121300 mavelertinib Drugs 0.000 claims description 6
- POOPTPRMXSYFRV-HNNXBMFYSA-N n-[(8s)-4-amino-5-quinolin-3-yl-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-8-yl]prop-2-enamide Chemical compound C1=CC=CC2=CC(C3=C4CC[C@@H](CN4C=4N=CN=C(C3=4)N)NC(=O)C=C)=CN=C21 POOPTPRMXSYFRV-HNNXBMFYSA-N 0.000 claims description 6
- KJBZQIKLKWQVLL-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[(7-methyl-7-azaspiro[3.5]nonan-2-yl)methoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1CN(C)CCC11CC(COC=2C(=CC3=C(NC=4C=C(Cl)C(F)=CC=4)N=CN=C3C=2)NC(=O)C=C)C1 KJBZQIKLKWQVLL-UHFFFAOYSA-N 0.000 claims description 6
- 229950008835 neratinib Drugs 0.000 claims description 6
- ZNHPZUKZSNBOSQ-BQYQJAHWSA-N neratinib Chemical compound C=12C=C(NC\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZNHPZUKZSNBOSQ-BQYQJAHWSA-N 0.000 claims description 6
- AZSRSNUQCUDCGG-UHFFFAOYSA-N propan-2-yl 2-[4-[2-(dimethylamino)ethyl-methylamino]-2-methoxy-5-(prop-2-enoylamino)anilino]-4-(1-methylindol-3-yl)pyrimidine-5-carboxylate Chemical compound C(C=C)(=O)NC=1C(=CC(=C(C=1)NC1=NC=C(C(=N1)C1=CN(C2=CC=CC=C12)C)C(=O)OC(C)C)OC)N(C)CCN(C)C AZSRSNUQCUDCGG-UHFFFAOYSA-N 0.000 claims description 6
- 229940075576 pyrotinib Drugs 0.000 claims description 6
- 201000011549 stomach cancer Diseases 0.000 claims description 6
- 229950008044 tarloxotinib bromide Drugs 0.000 claims description 6
- 229950006605 varlitinib Drugs 0.000 claims description 6
- NGFFVZQXSRKHBM-FKBYEOEOSA-N 5-[[(1r,1as,6br)-1-[6-(trifluoromethyl)-1h-benzimidazol-2-yl]-1a,6b-dihydro-1h-cyclopropa[b][1]benzofuran-5-yl]oxy]-3,4-dihydro-1h-1,8-naphthyridin-2-one Chemical compound N1C(=O)CCC2=C1N=CC=C2OC(C=C1[C@@H]23)=CC=C1O[C@@H]3[C@H]2C1=NC2=CC=C(C(F)(F)F)C=C2N1 NGFFVZQXSRKHBM-FKBYEOEOSA-N 0.000 claims description 5
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 5
- 208000006332 Choriocarcinoma Diseases 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 5
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims description 5
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 5
- 206010025323 Lymphomas Diseases 0.000 claims description 5
- 208000034578 Multiple myelomas Diseases 0.000 claims description 5
- 206010029260 Neuroblastoma Diseases 0.000 claims description 5
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 5
- 208000000035 Osteochondroma Diseases 0.000 claims description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 206010038389 Renal cancer Diseases 0.000 claims description 5
- 206010039491 Sarcoma Diseases 0.000 claims description 5
- 201000010208 Seminoma Diseases 0.000 claims description 5
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 5
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 5
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 5
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 5
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 5
- 208000017733 acquired polycythemia vera Diseases 0.000 claims description 5
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 5
- 229950008925 depatuxizumab mafodotin Drugs 0.000 claims description 5
- 201000004101 esophageal cancer Diseases 0.000 claims description 5
- 201000010175 gallbladder cancer Diseases 0.000 claims description 5
- 208000005017 glioblastoma Diseases 0.000 claims description 5
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 5
- 201000010982 kidney cancer Diseases 0.000 claims description 5
- 229950009767 lifirafenib Drugs 0.000 claims description 5
- 206010024627 liposarcoma Diseases 0.000 claims description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 5
- 201000001441 melanoma Diseases 0.000 claims description 5
- 208000025189 neoplasm of testis Diseases 0.000 claims description 5
- 201000008968 osteosarcoma Diseases 0.000 claims description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
- 208000037244 polycythemia vera Diseases 0.000 claims description 5
- 201000000849 skin cancer Diseases 0.000 claims description 5
- 201000003120 testicular cancer Diseases 0.000 claims description 5
- 229940121646 third-generation egfr tyrosine kinase inhibitor Drugs 0.000 claims description 5
- 208000013076 thyroid tumor Diseases 0.000 claims description 5
- 208000026517 ureter neoplasm Diseases 0.000 claims description 5
- 206010046766 uterine cancer Diseases 0.000 claims description 5
- QKDCLUARMDUUKN-XMMPIXPASA-N 6-ethyl-3-[4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]-5-[(3r)-1-prop-2-enoylpyrrolidin-3-yl]oxypyrazine-2-carboxamide Chemical compound N1=C(O[C@H]2CN(CC2)C(=O)C=C)C(CC)=NC(C(N)=O)=C1NC(C=C1)=CC=C1N(CC1)CCC1N1CCN(C)CC1 QKDCLUARMDUUKN-XMMPIXPASA-N 0.000 claims description 4
- 206010004593 Bile duct cancer Diseases 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- QHPVTCLSVVUPOF-UHFFFAOYSA-N N-[5-[[5-chloro-4-(naphthalen-2-ylamino)pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methylamino]-4-methoxyphenyl]prop-2-enamide Chemical compound COC1=C(NC2=NC=C(Cl)C(NC3=CC4=C(C=CC=C4)C=C3)=N2)C=C(NC(=O)C=C)C(=C1)N(C)CCN(C)C QHPVTCLSVVUPOF-UHFFFAOYSA-N 0.000 claims description 4
- UOFYSRZSLXWIQB-UHFFFAOYSA-N abivertinib Chemical compound C1CN(C)CCN1C(C(=C1)F)=CC=C1NC1=NC(OC=2C=C(NC(=O)C=C)C=CC=2)=C(C=CN2)C2=N1 UOFYSRZSLXWIQB-UHFFFAOYSA-N 0.000 claims description 4
- 208000026900 bile duct neoplasm Diseases 0.000 claims description 4
- 238000012217 deletion Methods 0.000 claims description 4
- 238000003780 insertion Methods 0.000 claims description 4
- 230000037431 insertion Effects 0.000 claims description 4
- 229950009708 naquotinib Drugs 0.000 claims description 4
- 230000037430 deletion Effects 0.000 claims description 3
- 102200048929 rs121913444 Human genes 0.000 claims description 3
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical compound CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 claims description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 2
- 229940050390 benzoate Drugs 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 claims description 2
- 229940050410 gluconate Drugs 0.000 claims description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 2
- 229940099584 lactobionate Drugs 0.000 claims description 2
- 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 claims description 2
- 229940070765 laurate Drugs 0.000 claims description 2
- 229940049920 malate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 claims description 2
- 239000002773 nucleotide Substances 0.000 claims description 2
- 125000003729 nucleotide group Chemical group 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- 229940049964 oleate Drugs 0.000 claims description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 102220014433 rs121913418 Human genes 0.000 claims description 2
- 102200048978 rs121913428 Human genes 0.000 claims description 2
- 102200048951 rs121913465 Human genes 0.000 claims description 2
- 102200048796 rs28929495 Human genes 0.000 claims description 2
- 102200048979 rs28929495 Human genes 0.000 claims description 2
- 102220014425 rs397517097 Human genes 0.000 claims description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 2
- 229960001860 salicylate Drugs 0.000 claims description 2
- 229940086735 succinate Drugs 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 229940070710 valerate Drugs 0.000 claims description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 2
- WKOLLVMJNQIZCI-UHFFFAOYSA-M vanillate Chemical compound COC1=CC(C([O-])=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-M 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
- 208000018084 Bone neoplasm Diseases 0.000 claims 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 12
- 230000000259 anti-tumor effect Effects 0.000 abstract description 3
- 230000035945 sensitivity Effects 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 238000005728 strengthening Methods 0.000 abstract 1
- 229960001611 alectinib Drugs 0.000 description 24
- KDGFLJKFZUIJMX-UHFFFAOYSA-N alectinib Chemical compound CCC1=CC=2C(=O)C(C3=CC=C(C=C3N3)C#N)=C3C(C)(C)C=2C=C1N(CC1)CCC1N1CCOCC1 KDGFLJKFZUIJMX-UHFFFAOYSA-N 0.000 description 24
- 201000011510 cancer Diseases 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 7
- 206010041823 squamous cell carcinoma Diseases 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 201000009030 Carcinoma Diseases 0.000 description 4
- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 208000008798 osteoma Diseases 0.000 description 4
- 108020000494 protein-tyrosine phosphatase Proteins 0.000 description 4
- 230000008261 resistance mechanism Effects 0.000 description 4
- 230000019491 signal transduction Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 3
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 238000011729 BALB/c nude mouse Methods 0.000 description 2
- 101150039808 Egfr gene Proteins 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000037437 driver mutation Effects 0.000 description 2
- 230000009422 growth inhibiting effect Effects 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 208000003849 large cell carcinoma Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 238000001543 one-way ANOVA Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 201000011476 ureteral benign neoplasm Diseases 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- ACSWJKPZXNIVMY-UHFFFAOYSA-N 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-3-fluorophenoxy]-n-methylpyridine-2-carboxamide;hydrochloride Chemical compound Cl.C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 ACSWJKPZXNIVMY-UHFFFAOYSA-N 0.000 description 1
- NGFFVZQXSRKHBM-UHFFFAOYSA-N 5-[[1-[6-(trifluoromethyl)-1h-benzimidazol-2-yl]-1a,6b-dihydro-1h-cyclopropa[b][1]benzofuran-5-yl]oxy]-3,4-dihydro-1h-1,8-naphthyridin-2-one Chemical compound N1C(=O)CCC2=C1N=CC=C2OC(C=C1C23)=CC=C1OC3C2C1=NC2=CC=C(C(F)(F)F)C=C2N1 NGFFVZQXSRKHBM-UHFFFAOYSA-N 0.000 description 1
- 101150023956 ALK gene Proteins 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010071975 EGFR gene mutation Diseases 0.000 description 1
- 101000686031 Homo sapiens Proto-oncogene tyrosine-protein kinase ROS 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
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- 206010050017 Lung cancer metastatic Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 206010048723 Multiple-drug resistance Diseases 0.000 description 1
- DOEOECWDNSEFDN-UHFFFAOYSA-N N-[5-[[4-(1-cyclopropylindol-3-yl)pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methylamino]-4-methoxyphenyl]prop-2-enamide Chemical compound C1(CC1)N1C=C(C2=CC=CC=C12)C1=NC(=NC=C1)NC=1C(=CC(=C(C=1)NC(C=C)=O)N(C)CCN(C)C)OC DOEOECWDNSEFDN-UHFFFAOYSA-N 0.000 description 1
- 108010032107 Non-Receptor Type 11 Protein Tyrosine Phosphatase Proteins 0.000 description 1
- 101150048674 PTPN11 gene Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 102100023347 Proto-oncogene tyrosine-protein kinase ROS Human genes 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 125000000218 acetic acid group Chemical class C(C)(=O)* 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 108700021358 erbB-1 Genes Proteins 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 238000011369 optimal treatment Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 229940121644 second-generation egfr tyrosine kinase inhibitor Drugs 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
- 230000004580 weight loss Effects 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
-
- 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
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines 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
- A61K31/495—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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- C07D471/10—Spiro-condensed systems
Definitions
- the invention belongs to the field of medicine, and relates to the use of a SHP2 inhibitor (SHP2 inhibitor) in the preparation of prevention or treatment of lung cancer patients after EGFR TKI treatment drug resistance.
- SHP2 inhibitor SHP2 inhibitor
- Lung cancer is the most common malignant tumor in China and even in the world.
- the World Health Organization International Agency for Research on Cancer (IARC) released the latest global cancer data in 2020, showing that the number of new lung cancers in the world is 2.2 million, accounting for 11.4% of the total cancer incidence, while China
- the number of new cases of lung cancer in China is 810,000 (17.9%), ranking first in the incidence rate; in terms of mortality, there are 710,000 lung cancer deaths in China, ranking first in the number of cancer deaths.
- Non-small cell lung cancer accounts for about 85% of all lung cancers, and about 75% of NSCLC patients are in advanced stages when they are discovered, and the 5-year survival rate is very low. For patients with advanced or metastatic NSCLC, there is still a great clinical need to choose an appropriate systemic treatment.
- NSCLC can be divided into squamous cell carcinoma and non-squamous cell carcinoma.
- Non-squamous cell carcinomas include adenocarcinoma, large cell carcinoma, and other subtypes of cell carcinoma.
- Patients with non-squamous cell carcinoma are further classified according to the presence or absence of driver mutation genes (EGFR mutation, ROS1 mutation, or ALK gene rearrangement), and the optimal treatment methods are different for different pathological types and stages.
- SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, containing two N-terminal Src homology 2 (SH2) domains, a protein tyrosine phosphatase (PTP) domain and a C-terminal .
- SH2 N-terminal Src homology 2
- PTP protein tyrosine phosphatase
- C-terminal C-terminal .
- the two conformations of the protein in the body are the active conformation of the open state and the inhibition phenomenon of the closed state, which is a common node for multiple activation of RAS signaling pathways. Almost all RTKs activate the RAS signaling pathway by activating SHP2.
- SHP2 is closely related to breast cancer, leukemia, lung cancer, liver cancer, gastric cancer, laryngeal cancer, oral cancer, and many other cancer types, and is the only proven proto-oncoprotein in the PTP family.
- the protein was proposed as a target as early as 2007, because its active site has a huge positive charge, it is difficult for charged molecules to pass through the cell membrane to reach the target position, so no suitable compound has been a candidate drug.
- breakthroughs have been made in the inhibitors of this target, but at present, there are no products of SHP2 inhibitors in the world, and a small number of drugs have entered the clinical stage.
- the EGFR gene is one of the most common driver genes in non-small cell lung cancer (NSCLC). About 50% of Chinese NSCLC patients have EGFR gene mutations. As the most commonly used targeted drug for treatment, EGFR TKI has made breakthrough progress. The first generation And the second-generation EGFR-TKI therapy has become the standard first-line treatment for patients with EGFR mutation-positive advanced NSCLC. The third-generation irreversible selective TKI is dedicated to overcoming T790M-mediated drug resistance and has shown encouraging efficacy. At the same time, it also has an inhibitory effect on EGFR sensitive mutations, and is expected to become the first-line treatment option.
- NSCLC non-small cell lung cancer
- a protein tyrosine phosphatase-2C (SHP2) inhibitor was developed in patent WO2020073949, and its structure is shown in formula (I):
- Patent WO2017161937 discloses a small molecule EGFR-TKI, the chemical name is: N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino) -2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide), its structure is shown in formula (II):
- the invention provides a use of a SHP2 inhibitor in the preparation of medicines for preventing or treating tumor diseases.
- the present invention also provides a use of the SHP2 inhibitor in the preparation of EGFR-TKI sensitizing drugs.
- the present invention additionally provides a use of a SHP2 inhibitor in the preparation of medicines for treating EGFR-TKI drug-resistant tumor diseases.
- the present invention also provides a use of a SHP2 inhibitor combined with EGFR-TKI in the preparation of a drug for preventing or treating tumor diseases.
- the tumor disease described in the present invention is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma , neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia , thyroid tumor, ureter tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma or choriocarcinoma; preferably lung cancer, more preferably non-small cell lung cancer.
- the non-small cell lung cancer is selected from squamous cell carcinoma or non-squamous cell carcinoma; preferably non-phosphorous cell carcinoma, wherein non-squamous cell carcinoma can be adenocarcinoma, large cell carcinoma and Other subtypes of cell carcinoma.
- the tumor disease is a tumor disease with EGFR mutation.
- the tumor disease of the EGFR mutation is non-small cell lung cancer
- the EGFR mutant preferably has a common or rare EGFR mutation or a combination thereof, wherein the common mutation is EGFR 19 exposition Sub-deletion (EGFR Del19), 858-site mutation (L858R); rare mutations are 289-site (G289V), 598-site (G598V), 709-site (E709X), 865-site (E865K), etc., preferably 719-site Point (G719X), 861 site (L861Q), 768 site (S768I), or any combination thereof, preferably EGFR L858R/T790M or EGFR Del19/T790M.
- the tumor disease with EGFR mutation has one or more EGFR mutations; preferably a point mutation or insertion of 1-18 nucleotides at exon 18, 19, 20 or 21 and/or deletions; more preferably mutations with EGFR L861Q, D761Y, L747S, S768I, G719C, G719D, G719S and exon 20 insertions.
- the tumor disease is an EGFR-TKI-resistant tumor disease, preferably a third-generation EGFR-TKI-resistant tumor disease, more preferably osimertinib, amitinib, norsertinib Tumor diseases resistant to Ni, Fumetinib, Ometinib, Avitinib, Befutinib, Lazatinib, CK101, ASK120067, ASP8273 or Nazatinib or its pharmaceutically acceptable salts, further Tumor diseases resistant to osimertinib or amitinib or their pharmaceutically acceptable salts are preferred.
- the tumor disease is EGFR-TKI-resistant lung cancer, preferably third-generation EGFR-TKI-resistant lung cancer, more preferably osimertinib, amitinib, norsertinib, Fumetinib, ometinib, avitinib, befutinib, lazatinib, CK101, ASK120067, ASP8273 or soloartinib or its pharmaceutically acceptable salts resistant lung cancer, more preferably Oxy Lung cancer resistant to tinib or alectinib or its pharmaceutically acceptable salts.
- the aforementioned tumor disease is EGFR-TKI-resistant non-small cell lung cancer, preferably third-generation EGFR-TKI-resistant non-small cell lung cancer, more preferably osimertinib, amitinib, Noseditinib, fumetinib, ometinib, avitinib, befutinib, lazatinib, CK101, ASK120067, ASP8273 or clawinib or its pharmaceutically acceptable salts.
- Small cell lung cancer more preferably non-small cell lung cancer resistant to osimertinib or alimertinib or a pharmaceutically acceptable salt thereof.
- the SHP2 inhibitor is a sensitizer of EGFR-TKI, which can prolong or treat drug resistance, eliminate the drug resistance phenomenon of EGFR-TKI, and show a good therapeutic effect.
- the SHP2 inhibitor is selected from compounds represented by formula (I) or pharmaceutically acceptable salts thereof:
- the pharmaceutically acceptable salt of the compound represented by the formula (I) is selected from hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetic acid Salt, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonic acid Salt, Isethionate, Maleate.
- the EGFR-TKI is selected from osimertinib (Oxitinib), gefitinib (gefitinib), erlotinib (erlotinib), olmutinib (Omotinib), icotinib ( BPI-2009H), pyrotinib, brigatinib, dacomitinib, afatinib, neratinib, lapatinib ), ABT-414, varlitinib (ASLAN001), HLX-07, tesevatinib (KD019), theliatinib (HMPL-309), epitinib succinate (epitinib succinate), S-222611, poziotinib (poziotinib), AST-2818, GNS-1480, mavelertinib (PF-06747775), AP-32788, AZD-37
- the EGFR-TKI is selected from olmutinib, afatinib, osimertinib, CK-101, erlotinib, icotinib, gefitinib or amitinib or a pharmaceutically acceptable salt thereof.
- the EGFR-TKI is alectinib or a pharmaceutically acceptable salt thereof.
- the EGFR-TKI is an acceptable salt of amotinib; preferably amotinib mesylate.
- the use of SHP2 inhibitors in combination with EGFR-TKI for the prevention or treatment of tumor diseases is characterized in that the tumor diseases have one or more EGFRs in EGFR L858R, T790M and Del19 mutation.
- the SHP2 inhibitor is selected from compounds represented by formula (I) or pharmaceutically acceptable salts thereof, and the EGFR-TKI is selected from osimertinib, gefitinib, erlotinib, olmutinib, icotinib, pyrotinib, brigatinib, dacomitinib, afatinib, neratinib, lapatinib, ABT-414, varlitinib, HLX-07, tesevatinib, theliatinib, epitinib succinate, S-222611, poziotinib, AST-2818, GNS-1480, mavelertinib, AP-32788, AZD-3759, josartinib, Sym -013, tesevatinib, allitinib tosylate, tarloxotinib bromide,
- the single dose of the SHP2 inhibitor is selected from 1-100 mg, preferably 1-50 mg, more preferably 1-20 mg, further preferably 3-20 mg, and even more preferably 3-15 mg.
- the administration frequency of the SHP2 inhibitor is selected from once a day, twice a day or three times a day.
- the administration frequency of the SHP2 inhibitor is once a day, and the single administration dose is selected from 3-20 mg, preferably 3 mg, 6 mg, 10 mg or 20 mg.
- the single dose range of SHP2 inhibitor is selected from 1 to 100 mg, and the exemplary dose is selected from 1 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5mg, 5.5mg, 6.0mg, 6.5mg, 7.0mg, 7.5mg, 8.0mg, 8.5mg, 9.0mg, 9.5mg, 10mg, 10.5mg, 11mg, 11.5mg, 12mg, 12.5mg, 13mg, 13.5mg , 14mg, 14.5mg, 15mg, 15.5mg, 16mg, 16.5mg, 17mg, 17.5mg, 18mg, 18.5mg, 19mg, 19.5mg, 20mg, 22.5mg, 25mg, 27.5mg, 30mg, 32.5mg, 35mg, 37.5mg , 40mg, 42.5mg, 45mg, 47.5mg,
- the dosage regimen of the SHP2 inhibitor is once a day, 1 mg once a day, 1.5 mg once a day, 2 mg once a day, 2.5 mg once a day, once a day Once, 3mg once a day, 3.5mg once a day, 4mg once a day, 4mg once a day, 4.5mg once a day, 5mg once a day, 5.5mg once a day, 6mg once a day, Once a day, 6.5mg once a day, 7mg once a day, 7mg once a day, 7.5mg once a day, 8mg once a day, 8.5mg once a day, 9mg once a day, once a day 9.5mg once a day, 10mg once a day, 10.5mg once a day, 11mg once a day, 11.5mg once a day, 12mg once a day, 12.5mg once a day,
- the single dose range of EGFR-KTI is selected from 1 to 500 mg, and the exemplary dose is selected from 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg , 20mg, 22.5mg, 25mg, 27.5mg, 30mg, 32.5mg, 35mg, 37.5mg, 40mg, 42.5mg, 45mg, 47.5mg, 50mg, 52.5mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 165mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg,
- the single dose of EGFR-TKI is selected from 20-500 mg.
- EGFR-TKI is administered once a day, and the single dosage is selected from 55 mg, 110 mg, 165 mg, 220 mg, and 260 mg.
- the dosage regimen of EGFR-TKI is 55 mg once a day, 110 mg once a day, 165 mg once a day, 220 mg once a day.
- the SHP2 inhibitor and EGFR-TKI are applied simultaneously, concurrently, independently or sequentially.
- the SHP2 inhibitor is administered simultaneously, concurrently, independently or sequentially with the EGFR-TKI after EGFR-TKI drug resistance.
- the EGFR-TKI is selected from osimertinib, gefitinib, erlotinib, olmutinib, icotinib, pyrotinib, brigatinib, dacomitinib, afatinib, neratinib, lapatinib, ABT-414 , varlitinib, HLX-07, tesevatinib, theliatinib, epitinib succinate, S-222611, poziotinib, AST-2818, GNS-1480, mavelertinib, AP-32788, AZD-3759, josartinib, Sym-013, tesevatinib, allitinib tosylate, tarloxotinib bromide, poziotinib, CK-101, Q
- the tumor disease is lung cancer, preferably non-small cell lung cancer; more preferably has one or more EGFR mutations in EGFR L858R, T790M and Del19 of non-small cell lung cancer.
- the EGFR-TKI is selected from osimertinib, gefitinib, erlotinib, olmutinib, icotinib, pyrotinib, brigatinib, dacomitinib, afatinib, neratinib, lapatinib, ABT-414, Varlitinib, HLX-07, tesevatinib, theliatinib, epitinib succinate, S-222611, poziotinib, AST-2818, GNS-1480, mavelertinib, AP-32788, AZD-3759, josartinib, Sym-013, tesevatinib, allitinib tosylate, tarloxotinib bromide , poziotinib, CK-101, QL
- the tumor disease is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer Cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, Multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer, or choriocarcinoma.
- the dosage regimen of the SHP2 inhibitor is once a day, 1 mg once a day, 1.5 mg once a day, 2 mg once a day, 2.5 mg once a day, once a day Once, 3mg once a day, 3.5mg once a day, 4mg once a day, 4mg once a day, 4.5mg once a day, 5mg once a day, 5.5mg once a day, 6mg once a day, Once a day, 6.5mg once a day, 7mg once a day, 7mg once a day, 7.5mg once a day, 8mg once a day, 8.5mg once a day, 9mg once a day, once a day 9.5mg once a day, 10mg once a day, 10.5mg once a day, 11mg once a day, 11.5mg once a day, 12mg once a day, 12.5mg once a day,
- the SHP2 inhibitor of the present invention is used in combination with EGFR-TKI, can eliminate the drug resistance phenomenon of EGFR-TKI, and show a good therapeutic effect, has stronger anti-tumor effect, and has no obvious toxic and side effects, in order to improve the efficacy of EGFR-TKI Sensitivity and treatment of tumor diseases provide new exploration and broad application prospects.
- Figure 3 The effect of drug A combined with alectinib on alectinib-resistant PC-9 human lung cancer xenografts.
- Drug A prepared according to the method disclosed in WO2020073949, 0.5% HPMC is used for drug preparation;
- Human lung cancer PC-9 cells were cultured in a single layer in vitro.
- the culture conditions were RPMI 1640 medium plus 10% fetal bovine serum, 100U/mL penicillin and 100 ⁇ g/mL streptomycin, and cultured in a 5% CO2 cell incubator at 37°C. Routine digestion with trypsin-EDTA was performed twice a week for passage. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and inoculated.
- mice Female, weighing 19-23g.
- Dosage Dosing cycle Route of administration 2-1 Amitinib 5mg/kg qd*29 p.o. 2-2 Almotinib + Drug A 5mg/kg+6mg/kg qd*29+qd*29 p.o+p.o
- T/C(%) (TT 0 )/(CC 0 ) ⁇ 100, where T and C are the tumor volumes at the end of the experiment, and T 0 and C 0 are the tumor volumes at the beginning of the experiment.
- TGI Tumor inhibition rate
- T ⁇ T 0 or C ⁇ C 0 it is defined as partial tumor regression (PR); if the tumor completely disappears, it is defined as complete tumor regression (CR).
- P value D77 The average tumor volume of the two groups was analyzed by T-test;
- the experimental results show that the average volume of the tumors on the 21st day, 49th day, and 77th day after continuous administration of alimertinib was 47mm 3 , 108mm 3 , and 406mm 3 , respectively, and the tumor volume showed a growth trend, showing certain drug resistance.
- the average tumor volume was 83mm 3 on the 77th day, which was statistically different from that of alectinib alone (p ⁇ 0.05), indicating that drug A could make alectinib prolonged drug resistance.
- the experimental time is calculated from the day of administration (day0);
- Drug A prepared according to the method disclosed in WO2020073949, 0.5% HPMC is used for drug preparation;
- Drug B Alectinib, prepared according to the method disclosed in WO2017161937, and acetic acid buffer solution at pH 4.18 is used for drug preparation;
- Alectinib-resistant PC-9 xenograft tumor This xenograft tumor model is an alectinib-resistant model constructed internally by the applicant.
- the PC-9 parental xenograft tumor model that is sensitive to alectinib is used to induce alectinib resistance.
- PC-20R xenografts were obtained after treatment.
- Dosage Dosing cycle Route of administration 1 solvent - qd*22 p.o. 2 Amitinib 20mg/kg qd*22 p.o. 3 Drug A 6mg/kg qd*22 p.o. 4 Almotinib + Drug A 20mg/kg+6mg/kg qd*22 p.o.
- the experimental index is to investigate the effect of the drug on tumor growth, and the specific index is T/C% or tumor inhibition rate TGI (%).
- T ⁇ T 0 or C ⁇ C 0 it is defined as partial tumor regression (PR); if the tumor completely disappears, it is defined as complete tumor regression (CR).
- the experimental data were analyzed and graphed with GraphPad Prism 8.4.3.
- the two-tailed T-test was used to compare the tumor volumes of the two groups.
- One-way ANOVA repeated measure is used for comparison among three or more groups. If there is a significant difference in F value, Dunnett’s should be used for multiple comparisons after ANOVA analysis. P ⁇ 0.05 was defined as a statistically significant difference.
- the experimental results showed that in the alimertinib-resistant PC-9 xenograft tumor model, the tumor growth of the alimertinib combined with drug A treatment group was more significantly inhibited than that of the single treatment group.
- the tumor volume of the combined drug group was 104mm 3 , which was significantly reduced compared with the tumor volumes of 852mm 3 and 615mm 3 in the alectinib and drug A single treatment groups (p ⁇ 0.05). It shows that the combination of drug A and alectinib can significantly inhibit the growth of alectinib-resistant transplanted tumors, and has a synergistic effect. During the treatment, no obvious abnormality was found in the body weight of the mice.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
提供了SHP2抑制剂联合EGFR-TKI治疗和预防肿瘤疾病的医药用途,以及SHP2抑制剂在制备治疗EGFR-TKI耐药肿瘤疾病的药物、制备EGFR-TKI增敏药物中的用途。具体而言,提供一种式(I)化合物或其可药用盐与EGFR-TKI药物在预防或治疗肿瘤疾病的药物中的用途。式(I)化合物或其可药用盐与EGFR-TKI药物联用,显示出更强的抗肿瘤作用,且无明显毒副作用,应用前景广阔。
Description
本发明属于医药领域,涉及SHP2抑制剂(SHP2inhibitor)在制备预防或治疗EGFR TKI治疗耐药后的肺癌患者中的用途。
肺癌是中国乃至全世界最常见的恶性肿瘤,世界卫生组织国际癌症研究机构(IARC)发布2020年全球最新癌症数据显示全球新增肺癌人数为220万,占总癌症发病率的11.4%,而中国的肺癌新发病例为81万(17.9%),位居发病率首位;从死亡率来看,中国肺癌死亡患者71万例,为癌症死亡人数首位。目前肺癌患者除了传统的放疗化疗等传统治疗外,近几年推出了更新的几代细胞毒性药物和靶向治疗药物,但是晚期肺癌患者、特别是没有已知的驱动突变基因或经EGFR抑制剂治疗后产生耐药的患者,治疗选择以及生存预后仍很差,晚期或转移性肺癌仍是一种有大量医疗需求未被满足的致死性疾病。
非小细胞肺癌(NSCLC)约占所有肺癌的85%,约75%的NSCLC患者发现时已处于中晚期,5年生存率很低。对于晚期或转移性NSCLC患者选择合适的系统性治疗方式仍在临床上存在很大的需求。NSCLC又可分为鳞状细胞癌与非鳞状细胞癌。非鳞状细胞癌包括腺癌、大细胞癌及其他亚型细胞癌。非鳞状细胞癌患者再按照有无驱动突变基因(EGFR突变、ROS1突变或ALK基因重排)进一步分类,不同病理类型,不同期的最佳治疗手段也不同。
SHP2是由PTPN11基因编码的非受体蛋白酪氨酸磷酸酶,含有两个N-末端Src同源2(SH2)结构域,一个蛋白酪氨酸磷酸酶(PTP)结构域和一个C-末端。该蛋白在体内的两个构象分别为张开状态的活性构象与闭合状态的抑制现象,为多条激活RAS信号通路的共有节点,几乎所有的RTK通过激活SHP2来启动RAS信号通路。SHP2与乳腺癌、白血病、肺癌、肝癌、胃癌、喉癌、口腔癌,以及其他多种癌症类型密切相关,为PTP家族中唯一被证实的原癌蛋白。虽然该蛋白早在2007年就被提出将它作为靶标,但由于其活性部位具有巨大的正电荷,而带电分子很难穿过细胞膜到达靶标位置,所以一直未有合适化合物成为候选药物。近几年由于变构抑制剂的出现,使该靶点抑制剂出现了突破性进展,但目前,全球SHP2抑制剂尚无产品上市,少量药物进入临床阶段。
EGFR基因是非小细胞肺癌(NSCLC)中最常见的驱动基因之一,约50%的中国NSCLC患者存在EGFR基因突变,EGFR TKI作为治疗最常用的靶向药物,取得了突破性进展,第一代和第二代EGFR-TKI治疗已成为EGFR突变阳性晚期NSCLC患者的标准一线治疗,第三代为不可逆的选择性TKI,致力于克服T790M介导的药物抵抗,显示出了令人鼓舞的疗效,同时对EGFR敏感突变亦有抑制作 用,有望成为一线治疗的选择。但无论那一代抑制剂,获得性耐药成为不可避免的问题,而目前,针对耐药的患者目前没有好的临床治疗方案。对于获得性耐药机制以及治疗方案研究始终方兴未艾,有研究表明,单个患者或许拥有多个耐药机制,使耐药组织成为多个交替驱动,耐药机制的异质性以及可塑性使得针对单一药物的治疗具有挑战性。由于SHP2介导多条RTK信号通路的转导,而三代EGFR-TKI耐药机制包括RTK信号通路的活化,故SHP2抑制剂的使用成为治疗或延长耐药发生的一种可能。
专利WO2020073949中开发出了一种蛋白酪氨酸磷酸酶-2C(SHP2)抑制剂,其结构如式(I)所示:
专利WO2017161937中公开了一种小分子EGFR-TKI,化学名称为:N-(5-((4-(1-环丙基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)丙烯酰基酰胺),其结构如式(II)所示:
发明内容
本发明提供了一种SHP2抑制剂在制备预防或治疗肿瘤疾病的药物中的用途。
本发明还提供了一种SHP2抑制剂在制备EGFR-TKI增敏药物中的用途。
本发明另外提供了一种SHP2抑制剂在制备治疗EGFR-TKI耐药肿瘤疾病的药物中的用途。
在本发明还提供了一种SHP2抑制剂联合EGFR-TKI在制备预防或治疗肿瘤疾病的药物中的用途。
本发明所述肿瘤疾病选自乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸 肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌或绒毛膜上皮癌;优选肺癌,更优选非小细胞肺癌。
在本发明优选的实施方案中,所述非小细胞肺癌选自鳞状细胞癌或非鳞状细胞癌;优选非磷状细胞癌,其中非鳞状细胞癌可以是腺癌、大细胞癌及其他亚型细胞癌。
在本发明优选的实施方案中,所述肿瘤疾病为EGFR突变的肿瘤疾病。
本发明优选的实施方案中,所述的EGFR突变的肿瘤疾病为非小细胞肺癌,优选具有EGFR突变体为含有常见的或罕见EGFR突变或其组合,其中所述的常见突变为EGFR 19外显子缺失(EGFR Del19)、858位点突变(L858R);罕见突变为289位点(G289V),598位点(G598V),709位点(E709X),865位点(E865K)等,优选719位点(G719X)、861位点(L861Q)、768位点(S768I),或其任意组合,优选为EGFR L858R/T790M或EGFR Del19/T790M。
本发明优选的实施方案中,所述的EGFR突变的肿瘤疾病具有一个或多个EGFR突变;优选具有外显子18、19、20或21处的1-18个核苷酸的点突变、插入和/或缺失;更优选具有EGFR L861Q、D761Y、L747S、S768I、G719C、G719D、G719S和外显子20插入的突变。
本发明优选的实施方案中,所述的肿瘤疾病为EGFR-TKI耐药的肿瘤疾病,优选第三代EGFR-TKI耐药的肿瘤疾病,更优选奥希替尼、阿美替尼、诺司替尼、伏美替尼、奥美替尼、艾维替尼、贝福替尼、拉泽替尼、CK101、ASK120067、ASP8273或纳扎替尼或其可药用盐耐药的肿瘤疾病,进一步优选奥希替尼或阿美替尼或其可药用盐耐药的肿瘤疾病。
本发明优选的实施方案中,所述的肿瘤疾病为EGFR-TKI耐药的肺癌,优选第三代EGFR-TKI耐药的肺癌,更优选奥希替尼、阿美替尼、诺司替尼、伏美替尼、奥美替尼、艾维替尼、贝福替尼、拉泽替尼、CK101、ASK120067、ASP8273或纳扎替尼或其可药用盐耐药的肺癌,进一步优选奥希替尼或阿美替尼或其可药用盐耐药的肺癌。
本发明优选的实施方案中,述的肿瘤疾病为EGFR-TKI耐药的非小细胞肺癌,优选第三代EGFR-TKI耐药的非小细胞肺癌,更优选奥希替尼、阿美替尼、诺司替尼、伏美替尼、奥美替尼、艾维替尼、贝福替尼、拉泽替尼、CK101、ASK120067、ASP8273或纳扎替尼或其可药用盐耐药的非小细胞肺癌,进一步优选奥希替尼或阿美替尼或其可药用盐耐药的非小细胞肺癌。
本发明优选的实施方案中,所述SHP2抑制剂为EGFR-TKI的增敏剂,能够延长或治疗耐药,消除EGFR-TKI的耐药现象,并显示出良好的治疗效果。
在本发明优选的实施方案中,所述SHP2抑制剂选自式(I)所示化合物或其可药用盐:
在本发明进一步优选的实施方案中,所述式(I)所示化合物的可药用盐选自盐酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、亚硫酸盐、乙酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、马来酸盐。苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐或月桂基磺酸盐。
在本发明优选的实施方案中,所述EGFR-TKI选自osimertinib(奥希替尼)、gefitinib(吉非替尼)、erlotinib(厄洛替尼)、olmutinib(奥莫替尼)、icotinib(BPI-2009H)、pyrotinib(吡咯替尼)、brigatinib(布加替尼)、dacomitinib(达可替尼)、afatinib(阿法替尼)、neratinib(来那替尼)、lapatinib(拉帕替尼)、ABT-414、varlitinib(ASLAN001)、HLX-07、tesevatinib(KD019)、theliatinib(HMPL-309)、epitinib succinate(琥珀酸依吡替尼)、S-222611、poziotinib(波齐替尼)、AST-2818、GNS-1480、mavelertinib(PF-06747775)、AP-32788、AZD-3759、nazartinib(纳扎替尼)、Sym-013、tesevatinib(KD019)、allitinib tosylate(AST-1306(TsOH))、tarloxotinib bromide(TH-4000)、poziotinib(波齐替尼)、CK-101、QL-1203、JNJ-61186372、SKLB-1028、TAS-121、Hemay-020、Hemay-022、NRC-2694-A、simotinib hydrochloride(盐酸西莫替尼)、SPH-1188-11、GR-1401、SYN-004、ABBV-221、MP-0274、GC-1118、BPI-15000、DBPR-112、Pirotinib(KBP-5209)、PB-357、lifirafenib(BGB-283)、SCT-200、QLNC-120、agerafenib hydrochloride(瑞戈非尼盐酸盐)或阿美替尼或其可药用盐。
在本发明进一步优选的实施方案中,所述EGFR-TKI选自olmutinib、afatinib、osimertinib、CK-101、erlotinib、icotinib、gefitinib或阿美替尼或其可药用盐。
在本发明进一步优选的实施方案中,所述EGFR-TKI为阿美替尼或其可药用盐。
在本发明进一步优选的实施方案中,所述的EGFR-TKI为阿美替尼可接受的盐;优选为甲磺酸阿美替尼。
在本发明进一步优选的实施方案中,SHP2抑制剂联合EGFR-TKI在制备预防或治疗肿瘤疾病中的用途,其特征在于所述的肿瘤疾病具有EGFR L858R、T790M和Del19中的一个或多个EGFR突变。
在本发明进一步优选的实施方案中,SHP2抑制剂选自式(I)所示化合物或其可药用盐,EGFR-TKI选自osimertinib、gefitinib、erlotinib、olmutinib、icotinib、 pyrotinib、brigatinib、dacomitinib、afatinib、neratinib、lapatinib、ABT-414、varlitinib、HLX-07、tesevatinib、theliatinib、epitinib succinate、S-222611、poziotinib、AST-2818、GNS-1480、mavelertinib、AP-32788、AZD-3759、nazartinib、Sym-013、tesevatinib、allitinib tosylate、tarloxotinib bromide、poziotinib、CK-101、QL-1203、JNJ-61186372、SKLB-1028、TAS-121、Hemay-020、Hemay-022、NRC-2694-A、simotinib hydrochloride、SPH-1188-11、GR-1401、SYN-004、ABBV-221、MP-0274、GC-1118、BPI-15000、DBPR-112、Pirotinib、PB-357、lifirafenib、SCT-200、QLNC-120、agerafenib hydrochloride或阿美替尼或其可药用盐。
在本发明进一步优选的实施方案中,SHP2抑制剂的单次给药剂量范围选自1~100mg,优选1~50mg,更优选1~20mg,进一步优选3~20mg,更进一步优选3~15mg。
在本发明进一步优选的实施方案中,SHP2抑制剂的给药频率选自一日一次、一日二次或一日三次。
在本发明进一步优选的实施方案中,SHP2抑制剂的给药频次为一日一次,单次给药剂量选自3~20mg,优选为3mg、6mg、10mg或20mg。
在本发明优选的实施方案中,SHP2抑制剂的单次给药剂量范围选自1~100mg,示例性的剂量选自1mg、1.5mg、2.0mg、2.5mg、3mg、3.5mg、4mg、4.5mg、5mg、5.5mg、6.0mg、6.5mg、7.0mg、7.5mg、8.0mg、8.5mg、9.0mg、9.5mg、10mg、10.5mg、11mg、11.5mg、12mg、12.5mg、13mg、13.5mg、14mg、14.5mg、15mg、15.5mg、16mg、16.5mg、17mg、17.5mg、18mg、18.5mg、19mg、19.5mg、20mg、22.5mg、25mg、27.5mg、30mg、32.5mg、35mg、37.5mg、40mg、42.5mg、45mg、47.5mg、50mg、52.5mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg。
在本发明进一步优选的实施方案中,SHP2抑制剂的给药方案为一日一次,一次1mg、一日一次,一次1.5mg、一日一次,一次2mg、一日一次,一次2.5mg、一日一次,一次3mg、一日一次,一次3.5mg、一日一次,一次4mg、一日一次,一次4.5mg、一日一次,一次5mg、一日一次,一次5.5mg、一日一次,一次6mg、一日一次,一次6.5mg、一日一次,一次7mg、一日一次,一次7.5mg、一日一次,一次8mg、一日一次,一次8.5mg、一日一次,一次9mg、一日一次,一次9.5mg、一日一次,一次10mg、一日一次,一次10.5mg、一日一次,一次11mg、一日一次,一次11.5mg、一日一次,一次12mg、一日一次,一次12.5mg、一日一次,一次13mg、一日一次,一次13.5mg、一日一次,一次14mg、一日一次,一次14.5mg、一日一次,一次15mg、一日一次,一次15.5mg、一日一次,一次16mg、一日一次,一次16.5mg、一日一次,一次17mg、一日一次,一次17.5mg、一日一次,一次18mg、一日一次,一次19.5mg、一日一次,一次20mg。
在本发明优选的实施方案中,EGFR-KTI的单次给药剂量范围选自1~500mg, 示例性的剂量选自1mg、2.5mg、5mg、7.5mg、10mg、12.5mg、15mg、17.5mg、20mg、22.5mg、25mg、27.5mg、30mg、32.5mg、35mg、37.5mg、40mg、42.5mg、45mg、47.5mg、50mg、52.5mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、120mg、130mg、140mg、150mg、160mg、165mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、260mg、270mg、275mg、280mg、290mg、300mg、330mg、385mg、440mg、495mg。
在本发明进一步优选的实施方案中,EGFR-TKI的单次给药剂量范围选自20~500mg。
在本发明进一步优选的实施方案中,EGFR-TKI的单次给药剂量范围选自50~300mg,进一步优选55mg、110mg或165mg。
在本发明进一步优选的实施方案中,EGFR-TKI的给药频次选自一日一次、一日二次或一日三次。
在本发明进一步优选的实施方案中,EGFR-TKI一日一次给药,单次给药剂量选自55mg、110mg、165mg、220mg、260mg。
在本发明进一步优选的实施方案中,EGFR-TKI的给药方案为一日一次,一次55mg、一日一次,一次110mg、一日一次,一次165mg、一日一次,一次220mg。
在本发明进一步优选的实施方案中,SHP2抑制剂与EGFR-TKI剂量比选自1:50~1:5,优选1:40~1:2,更优选1:20~1:5。
在本发明进一步优选的实施方案中,式(I)所示化合物或其可药用盐与阿美替尼或其可药用盐的剂量比选自1:40~1:2,优选1:20~1:2,更优选1:20~1:5,更进一步优选更优选1:15~1:5。
在本发明进一步优选的实施方案中,SHP2抑制剂与EGFR-TKI同时、并行、独立或按顺序地应用。
在本发明进一步优选的实施方案中,SHP2抑制剂在EGFR-TKI耐药后与EGFR-TKI同时、并行、独立或按顺序给药。
本发明还提供了一种药物组合物,其包含:
(a)一个或多个SHP2抑制剂;
(b)一个或多个EGFR-TKI。
在本发明进一步优选的实施方案中,根据本发明的药物组合物,所述的SHP2抑制剂选自式(I)化合物或其可药用盐:
在本发明进一步优选的实施方案中,根据本发明的药物组合物,所述EGFR-TKI选自osimertinib、gefitinib、erlotinib、olmutinib、icotinib、pyrotinib、brigatinib、dacomitinib、afatinib、neratinib、lapatinib、ABT-414、varlitinib、HLX-07、tesevatinib、theliatinib、epitinib succinate、S-222611、poziotinib、AST-2818、GNS-1480、mavelertinib、AP-32788、AZD-3759、nazartinib、Sym-013、tesevatinib、allitinib tosylate、tarloxotinib bromide、poziotinib、CK-101、QL-1203、JNJ-61186372、SKLB-1028、TAS-121、Hemay-020、Hemay-022、NRC-2694-A、simotinib hydrochloride、SPH-1188-11、GR-1401、SYN-004、ABBV-221、MP-0274、GC-1118、BPI-15000、DBPR-112、Pirotinib、PB-357、lifirafenib、SCT-200、QLNC-120、agerafenib hydrochloride或阿美替尼或其可药用盐。
本发明还提供了所述药物组合物用于治疗肿瘤疾病的用途。
本发明还提供了所述药物组合物在制备预防或治疗肿瘤疾病的药物中的用途。
在本发明优选的实施方案中,根据本发明药物组合物的用途,所述肿瘤疾病选自乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌或绒毛膜上皮癌。
在本发明进一步优选的实施方案中,根据本发明药物组合物的用途,所述肿瘤疾病为肺癌,优选为非小细胞肺癌;更优选具有EGFR L858R、T790M和Del19中的一个或多个EGFR突变的非小细胞肺癌肺癌。
在本发明进一步优选的实施方案中,SHP2抑制剂的给药方案为一日一次,一次1mg、一日一次,一次1.5mg、一日一次,一次2mg、一日一次,一次2.5mg、一日一次,一次3mg、一日一次,一次3.5mg、一日一次,一次4mg、一日一次,一次4.5mg、一日一次,一次5mg、一日一次,一次5.5mg、一日一次,一次6mg、一日一次,一次6.5mg、一日一次,一次7mg、一日一次,一次7.5mg、一日一次,一次8mg、一日一次,一次8.5mg、一日一次,一次9mg、一日一次,一次9.5mg、一日一次,一次10mg、一日一次,一次10.5mg、一日一次,一次11mg、一日一次,一次11.5mg、一日一次,一次12mg、一日一次,一次12.5mg、一日一次,一次13mg、一日一次,一次13.5mg、一日一次,一次14mg、一日一次,一次14.5mg、一日一次,一次15mg、一日一次,一次15.5mg、一日一次,一次16mg、一日一次,一次16.5mg、一日一次,一次17mg、一日一次,一次17.5mg、一日一次,一次18mg、一日一次,一次19.5mg、一日一次,一次20mg。
在本发明进一步优选的实施方案中,EGFR-TKI的给药方案为一日一次,一次55mg、一日一次,一次110mg、一日一次,一次165mg、一日一次,一次220mg。
本发明还提供了一种联合制剂,其包含:
(a)一个或多个SHP2抑制剂;
(b)一个或多个EGFR-TKI。
在本发明优选的实施方案中,根据本发明的联合制剂,所述SHP2抑制剂选自式(I)化合物或其可药用盐:
在本发明进一步优选的实施方案中,根据本发明的联合制剂,所述EGFR-TKI选自osimertinib、gefitinib、erlotinib、olmutinib、icotinib、pyrotinib、brigatinib、dacomitinib、afatinib、neratinib、lapatinib、ABT-414、varlitinib、HLX-07、tesevatinib、theliatinib、epitinib succinate、S-222611、poziotinib、AST-2818、GNS-1480、mavelertinib、AP-32788、AZD-3759、nazartinib、Sym-013、tesevatinib、allitinib tosylate、tarloxotinib bromide、poziotinib、CK-101、QL-1203、JNJ-61186372、SKLB-1028、TAS-121、Hemay-020、Hemay-022、NRC-2694-A、simotinib hydrochloride、SPH-1188-11、GR-1401、SYN-004、ABBV-221、MP-0274、GC-1118、BPI-15000、DBPR-112、Pirotinib、PB-357、lifirafenib、SCT-200、QLNC-120、agerafenib hydrochloride或阿美替尼或其可药用盐。
本发明还提供了所述联合制剂用于治疗肿瘤疾病的用途。
本发明还提供了所述联合制剂在制备预防或治疗肿瘤疾病的药物中的用途。
在本发明优选的实施方案中,根据本发明联合制剂的用途,所述肿瘤疾病选自乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌或绒毛膜上皮癌。
在本发明进一步优选的实施方案中,根据本发明联合制剂的用途,所述肿瘤疾病为肺癌,优选为非小细胞肺癌。
在本发明进一步优选的实施方案中,SHP2抑制剂的给药方案为一日一次,一次1mg、一日一次,一次1.5mg、一日一次,一次2mg、一日一次,一次2.5mg、一日一次,一次3mg、一日一次,一次3.5mg、一日一次,一次4mg、一日一次,一次4.5mg、一日一次,一次5mg、一日一次,一次5.5mg、一日一次,一次6mg、一日一次,一次6.5mg、一日一次,一次7mg、一日一次,一次7.5mg、一日一次,一次8mg、一日一次,一次8.5mg、一日一次,一次9mg、一日一次,一次 9.5mg、一日一次,一次10mg、一日一次,一次10.5mg、一日一次,一次11mg、一日一次,一次11.5mg、一日一次,一次12mg、一日一次,一次12.5mg、一日一次,一次13mg、一日一次,一次13.5mg、一日一次,一次14mg、一日一次,一次14.5mg、一日一次,一次15mg、一日一次,一次15.5mg、一日一次,一次16mg、一日一次,一次16.5mg、一日一次,一次17mg、一日一次,一次17.5mg、一日一次,一次18mg、一日一次,一次19.5mg、一日一次,一次20mg。
在本发明进一步优选的实施方案中,EGFR-TKI的给药方案为一日一次,一次55mg、一日一次,一次110mg、一日一次,一次165mg、一日一次,一次220mg。
本发明还提供了预防或治疗肿瘤疾病的方法,包括施用有效剂量的下列化合物的组合:
(a)一个或多个SHP2抑制剂;
(b)一个或多个EGFR-TKI;
在本发明进一步优选的实施方案中,SHP2抑制剂的给药方案为一日一次,一次1mg、一日一次,一次1.5mg、一日一次,一次2mg、一日一次,一次2.5mg、一日一次,一次3mg、一日一次,一次3.5mg、一日一次,一次4mg、一日一次,一次4.5mg、一日一次,一次5mg、一日一次,一次5.5mg、一日一次,一次6mg、一日一次,一次6.5mg、一日一次,一次7mg、一日一次,一次7.5mg、一日一次,一次8mg、一日一次,一次8.5mg、一日一次,一次9mg、一日一次,一次9.5mg、一日一次,一次10mg、一日一次,一次10.5mg、一日一次,一次11mg、一日一次,一次11.5mg、一日一次,一次12mg、一日一次,一次12.5mg、一日一次,一次13mg、一日一次,一次13.5mg、一日一次,一次14mg、一日一次,一次14.5mg、一日一次,一次15mg、一日一次,一次15.5mg、一日一次,一次16mg、一日一次,一次16.5mg、一日一次,一次17mg、一日一次,一次17.5mg、一日一次,一次18mg、一日一次,一次19.5mg、一日一次,一次20mg。
在本发明进一步优选的实施方案中,EGFR-TKI的给药方案为一日一次,一次55mg、一日一次,一次110mg、一日一次,一次165mg、一日一次,一次220mg。
SHP2抑制剂与EGFR-TKI同时、并行、独立或按顺序地给药,优选地,SHP2抑制剂在EGFR-TKI耐药后与EGFR-TKI同时、并行、独立或按顺序给药。
在本发明优选的实施方案中,根据本发明预防或治疗肿瘤疾病的方法,其中EGFR-TKI选自osimertinib、gefitinib、erlotinib、olmutinib、icotinib、pyrotinib、brigatinib、dacomitinib、afatinib、neratinib、lapatinib、ABT-414、varlitinib、HLX-07、tesevatinib、theliatinib、epitinib succinate、S-222611、poziotinib、AST-2818、GNS-1480、mavelertinib、AP-32788、AZD-3759、nazartinib、Sym-013、tesevatinib、allitinib tosylate、tarloxotinib bromide、poziotinib、CK-101、QL-1203、JNJ-61186372、SKLB-1028、TAS-121、Hemay-020、Hemay-022、NRC-2694-A、simotinib hydrochloride、SPH-1188-11、GR-1401、SYN-004、ABBV-221、MP-0274、GC-1118、 BPI-15000、DBPR-112、Pirotinib、PB-357、lifirafenib、SCT-200、QLNC-120、agerafenib hydrochloride或阿美替尼或其可药用盐。
在本发明进一步优选的实施方案中,根据本发明预防或治疗肿瘤疾病的方法,其中SHP2抑制剂选自式(I)化合物或其可药用盐:
在本发明进一步优选的实施方案中,根据本发明预防或治疗肿瘤疾病的方法,所述肿瘤疾病选自乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌或绒毛膜上皮癌;优选肺癌,更优选非小细胞肺癌。
如无相反解释,本发明中术语具有如下含义:
本发明中所述的“联合”是一种给药方式,是指在一定时间期限内给予至少一种剂量的SHP2抑制剂和至少一种剂量的EGFR-TKI,其中两种物质都显示药理学作用。所述的时间期限可以是一个给药周期内,优选4周内,3周内,2周内,1周内,或24小时以内。可以同时或依次给予SHP2抑制剂和EGFR-TKI。这种期限包括这样的治疗,其中通过相同给药途径或不同给药途径给予SHP2抑制剂和EGFR-TKI。
术语“有效剂量”指在哺乳动物中有效治疗疾病或病症的药物量。在癌症的情况中,治疗有效剂量的药物可减少癌细胞的数目;缩小肿瘤的尺寸;抑制(即一定程度的减缓和优选阻止)癌细胞浸润到周围器官中;抑制(即一定程度的减缓和优选阻止)肿瘤转移;一定程度的抑制肿瘤生长;和/或一定程度的减轻一种或多种与该病症有关的症状。根据药物可阻止现有癌细胞生长和/或杀死现有癌细胞的程度,它可以是细胞抑制性的和/或细胞毒性的。对于癌症治疗,可通过评估存活持续时间、无进展存活(PFS)持续时间、响应率(RR)、响应持续时间和/或生活质量来测量体内功效。
本发明SHP2抑制剂与EGFR-TKI联用,可消除EGFR-TKI的耐药现象,并显示出良好的治疗效果,具有更强的抗肿瘤作用,且无明显毒副作用,为提高EGFR-TKI的敏感性、肿瘤疾病的治疗方法,提供了新的探索,应用前景广阔。
图1.药物A对阿美替尼耐药后PC-9人源肺癌移植瘤的疗效。
图2.药物A对阿美替尼耐药后PC-9荷瘤鼠体重的影响。
图3.药物A联合阿美替尼对阿美替尼耐药PC-9人源肺癌移植瘤的疗效。
图4.药物A联合阿美替尼对阿美替尼耐药后PC-9荷瘤鼠体重的影响。
以下将结合实施例更详细地解释本发明,本发明的实施例仅用于说明本发明的技术方案,并非限定本发明的实质和范围。
实施例1
实验目的
评价式(I)所示化合物(药物A)对阿美替尼耐药后PC-9人源肺癌小鼠异种移植瘤的抑制作用。
实验材料
药物A:依据WO2020073949公开方法制备,药物配制用0.5%HPMC;
药物B:阿美替尼,依据WO2017161937公开方法制备,药物配制用PH4.18乙酸缓冲液;
人肺癌PC-9细胞,体外单层培养,培养条件为RPMI 1640培养基中加10%胎牛血清,100U/mL青霉素和100μg/mL链霉素,37℃5%CO2细胞培养箱中培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80%-90%,数量到达要求时,收取细胞,计数,接种。
BALB/c裸小鼠,雌性,体重19-23g。
实验方法
将5×10
6人肺癌细胞PC-9细胞注入裸小鼠右上背部皮下,待肿瘤生长至合适体积后,挑选负荷肿瘤体积为100-200mm
3的动物进行阿美替尼耐药诱导,肿瘤出现耐药后添加药物A进行治疗。小鼠灌胃给药(p.o),每日1次(qd);给药体积10mL/kg;溶剂组给予相同体积的“溶剂”(PH4.18乙酸缓冲液);具体给药剂量和给药方案见表1。测肿瘤体积,称小鼠体重,记录数据:
表1.药物A治疗阿美替尼耐药PC-9模型中的给药方案
第一阶段(诱导阶段)
组别 | 分组 | 给药剂量 | 给药周期 | 给药途径 |
1 | 溶剂 | - | qd*21 | p.o |
2 | 阿美替尼 | 5mg/kg | qd*48 | p.o |
第二阶段(治疗阶段)
组别 | 分组 | 给药剂量 | 给药周期 | 给药途径 |
2-1 | 阿美替尼 | 5mg/kg | qd*29 | p.o |
2-2 | 阿美替尼+药物A | 5mg/kg+6mg/kg | qd*29+qd*29 | p.o+p.o |
实验参数
实验指标为考察药物对肿瘤生长的影响,具体指标为T/C%或抑瘤率TGI(%)。
用游标卡尺测量肿瘤直径,肿瘤体积(V)计算公式为:V=1/2×a×b
2,其中a、b分别表示长、宽。
T/C(%)=(T-T
0)/(C-C
0)×100,其中T、C为实验结束时的肿瘤体积,T
0、C
0为实验开始时的肿瘤体积。
抑瘤率(TGI)(%)=100-T/C(%)。
当肿瘤出现消退时,抑瘤率(TGI)(%)=100-(T-T
0)/T
0×100
如果肿瘤比起始体积缩小,即T<T
0或C<C
0时,即定义为肿瘤部分消退(PR);如果肿瘤完全消失,即定义为肿瘤完全消退(CR)。
实验结束,达到实验终点、或肿瘤体积达到2000mm
3,CO
2麻醉处死物,随后解剖取瘤、拍照。
数据处理
实验数据用GraphPad Prism 8.4.3分析、作图。二组肿瘤体积之间比较采用双尾T检验。三组或多组间比较用one-way ANOVA repeated measure,如果F值有显著性差异,应在ANOVA分析之后使用Dunnett’s进行多重比较。P<0.05定义为差异有统计学显著性。
实验结果
药物A对阿美替尼耐药后PC-9人源肺癌移植瘤的疗效如表2,及图1所示:
表2.药物A对阿美替尼耐药PC-9模型的生长抑制作用
P值D77:两组肿瘤平均体积运用T-test分析所得数值;
实验结果表明,阿美替尼连续给药至第21天、第49天、第77天时的肿瘤平均体积分别为47mm
3、108mm
3、406mm
3,肿瘤体积呈现生长趋势,显示出一定的耐药现象,而在耐药生长阶段添加药物A联合治疗,第77天时肿瘤平均体积为83mm
3,与阿美替尼单独治疗组相比具有统计学差异(p<0.05),表明药物A可以使阿美替尼的耐药时间延长。
药物A对阿美替尼耐药后PC-9荷瘤鼠体重的影响如表3,及附图2所示:
表3.第二阶段各组动物的体重变化
a:给药当天(day0)开始计算实验时间;
b:数据以“平均值±标准误差”表示
结果表明,整个实验过程中荷瘤小鼠对药物剂量均能很好耐受,没有体重明显减轻症状发生。
结论:总体而言,药物A联合阿美替尼可以延长耐药的发生,显示出更强的抗肿瘤作用,且未表现出明显毒副作用。
实施例2
实验目的
评价式(I)所示化合物(药物A)与阿美替尼联合用药对于阿美替尼耐药的PC-9人源肺癌小鼠异种移植瘤的抑制作用。
实验材料
药物A:依据WO2020073949公开方法制备,药物配制用0.5%HPMC;
药物B:阿美替尼,依据WO2017161937公开方法制备,药物配制用PH4.18乙酸缓冲液;
阿美替尼耐药PC-9移植瘤:该移植瘤模型为申请人内部构建的阿美替尼耐药模型,通过采用阿美替尼长期处理敏感的PC-9亲本移植瘤模型诱导对阿美替尼耐药后获得PC-20R移植瘤。
BALB/c裸小鼠,雌性,体重19-23g。
实验方法
将诱导的阿美替尼耐药移植瘤(PC-20R)使用手术剪剪成1-2mm大小的肿瘤组织,采用穿刺针接种于裸小鼠右上背部皮下,待肿瘤生长至合适体积后,挑 选负荷肿瘤体积为100-200mm
3的动物进行分组给药。具体给药剂量和给药方案见表4。测肿瘤体积,称小鼠体重,记录数据:
表4.药物A联合阿美替尼治疗阿美替尼耐药PC-9模型中的给药方案
组别 | 分组 | 给药剂量 | 给药周期 | 给药途径 |
1 | 溶剂 | - | qd*22 | p.o |
2 | 阿美替尼 | 20mg/kg | qd*22 | p.o |
3 | 药物A | 6mg/kg | qd*22 | p.o |
4 | 阿美替尼+药物A | 20mg/kg+6mg/kg | qd*22 | p.o |
实验参数
实验指标为考察药物对肿瘤生长的影响,具体指标为T/C%或抑瘤率TGI(%)。
用游标卡尺测量肿瘤直径,肿瘤体积(V)计算公式为:V=1/2×a×b
2,其中a、b分别表示长、宽。
T/C(%)=(T-T
0)/(C-C
0)×100,其中T、C为实验结束时的肿瘤体积,T
0、C
0为实验开始时的肿瘤体积。
抑瘤率(TGI)(%)=100-T/C(%)。
当肿瘤出现消退时,抑瘤率(TGI)(%)=100-(T-T
0)/T
0×100
如果肿瘤比起始体积缩小,即T<T
0或C<C
0时,即定义为肿瘤部分消退(PR);如果肿瘤完全消失,即定义为肿瘤完全消退(CR)。
实验结束,达到实验终点、或肿瘤体积达到2000mm
3,CO
2麻醉处死物,随后解剖取瘤、拍照。
数据处理
实验数据用GraphPad Prism 8.4.3分析、作图。二组肿瘤体积之间比较采用双尾T检验。三组或多组间比较用one-way ANOVA repeated measure,如果F值有显著性差异,应在ANOVA分析之后使用Dunnett’s进行多重比较。P<0.05定义为差异有统计学显著性。
实验结果
药物A联合阿美替尼对阿美替尼耐药PC-9人源肺癌移植瘤的疗效如表5,及图3-4所示:
表5.药物A联合阿美替尼对阿美替尼耐药PC-9模型的生长抑制作用
实验结果表明,在阿美替尼耐药的PC-9移植瘤模型中,阿美替尼联合药物A治疗组的肿瘤的生长较单独治疗组受到更加显著的抑制作用。连续给药22天后,联合用药组的肿瘤体积为104mm
3,较阿美替尼和药物A单独治疗组的肿瘤体积852mm
3、615mm
3显著减少,具有统计学差异(p<0.05)。表明药物A与阿美替尼联合用药能够显著地抑制阿美替尼耐药移植瘤的生长,具有协同作用。在治疗过程中,小鼠体重未见明显异常。
Claims (16)
- 根据权利要求1所述的用途,其特征在于,所述肿瘤疾病选自乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌或绒毛膜上皮癌;优选肺癌;更优选非小细胞肺癌。
- 根据权利要求1或2所述的用途,其特征在于,所述的肿瘤疾病具有一个或多个EGFR突变;优选具有外显子18、19、20或21处的1-18个核苷酸的点突变、插入和/或缺失;更优选具有EGFR 19外显子缺失、858位点、289位点,598位点,709位点,865位点,优选719位点、861位点或者768位点突变;进一步优选具有EGFR L858R、T790M、Del19、T790M L861Q、D761Y、L747S、S768I、G719C、G719D、G719S和外显子20插入中的一个或多个突变。
- 根据权利要求3所述的用途,其特征在于,所述的肿瘤疾病为EGFR-TKI耐药的肿瘤疾病;优选EGFR-TKI耐药的非小细胞肺癌;更优选第三代EGFR-TKI耐药的非小细胞肺癌;进一步优选奥希替尼、阿美替尼、诺司替尼、伏美替尼、奥美替尼、艾维替尼、贝福替尼、拉泽替尼、CK101、ASK120067、ASP8273或纳扎替尼或其可药用盐耐药的非小细胞肺癌;更进一步优选奥希替尼或阿美替尼或其可药用盐耐药的非小细胞肺癌。
- 根据权利要求1所述的用途,其特征在于,EGFR-TKI选自osimertinib、gefitinib、erlotinib、olmutinib、icotinib、pyrotinib、brigatinib、dacomitinib、afatinib、neratinib、lapatinib、ABT-414、varlitinib、HLX-07、tesevatinib、theliatinib、epitinibsuccinate、S-222611、poziotinib、AST-2818、GNS-1480、mavelertinib、AP-32788、AZD-3759、nazartinib、Sym-013、tesevatinib、allitinib tosylate、tarloxotinib bromide、poziotinib、CK-101、QL-1203、JNJ-61186372、SKLB-1028、TAS-121、Hemay-020、Hemay-022、NRC-2694-A、simotinib hydrochloride、SPH-1188-11、GR-1401、SYN-004、ABBV-221、MP-0274、GC-1118、BPI-15000、DBPR-112、Pirotinib、PB-357、lifirafenib、SCT-200、QLNC-120、agerafenib hydrochloride或阿美替尼;优选olmutinib、afatinib、osimertinib、CK-101、erlotinib、icotinib、gefitinib或阿美替尼;最优选阿美替尼;优选甲磺酸阿美替尼。
- 根据权利要求1-5任一项所述的用途,其特征在于所述的EGFR-TKI为阿美替尼或其可药用盐,所述的肿瘤疾病具有EGFR L858R、T790M和Del19中的一个或多个EGFR突变。
- 根据权利要求1-5任一项所述的用途,其特征在于,SHP2抑制剂的单次给药剂量范围选自1~100mg;优选1~20mg;更优选3~15mg。
- 根据权利要求1-5任一项所述的用途,其特征在于,SHP2抑制剂的给药频率选自一日一次、一日二次或一日三次。
- 根据权利要求1-5任一项所述的用途,其特征在于,SHP2抑制剂的单次给药剂量为3mg,每日一次、单次给药剂量为6mg,每日一次、单次给药剂量为10mg,每日一次或单次给药剂量为20mg,每日一次。
- 根据权利要求1-5任一项所述的用途,其特征在于,EGFR-TKI的单次给药剂量范围选自1~500mg,优选20~500mg,更优选50~300mg,进一步优选55mg、110mg、165mg或220mg。
- 根据权利要求1-5任一项所述的用途,其特征在于,EGFR-TKI的给药频次选自一日一次、一日二次或一日三次。
- 根据权利要求1-5任一项所述的用途,其特征在于,EGFR-TKI单次给药剂量为55mg,每日一次、单次给药剂量为110mg,每日一次、单次给药剂量为165mg,每日一次或单次给药剂量为220mg,每日一次。
- 根据权利要求1-5任一项所述的用途,其特征在于,式(I)所示化合物或其可药用盐与阿美替尼或其可药用盐的剂量比选自1:40~1:2;优选1:20~1:2;更优选1:20~1:5。
- 根据权利要求1-5任一项所述的用途,其特征在于,SHP2抑制剂与EGFR-TKI同时、并行、独立或按顺序给药,优选地,SHP2抑制剂在EGFR-TKI耐药后与EGFR-TKI同时、并行、独立或按顺序给药。
- 一种药物组合物,其特征在于,包括有效剂量的式(I)所示化合物或其可药用盐以及EGFR-TKI或其可药用盐;优选为式(I)所示化合物或其可药用盐以及阿美替尼或其可药用盐。
- 根据权利要求15所述的药物组合物,其特征在于,在制备预防或治疗非小细胞肺癌的药物中的用途;优选具有EGFR L858R、T790M和Del19中的一个或多个EGFR突变的非小细胞肺癌肺癌。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202280063878.2A CN118019537A (zh) | 2021-09-28 | 2022-09-28 | Shp2抑制剂联合egfr-tki治疗和预防肿瘤疾病的医药用途 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111141630.7 | 2021-09-28 | ||
CN202111141630 | 2021-09-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023051606A1 true WO2023051606A1 (zh) | 2023-04-06 |
Family
ID=85781327
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2022/122104 WO2023051606A1 (zh) | 2021-09-28 | 2022-09-28 | Shp2抑制剂联合egfr-tki治疗和预防肿瘤疾病的医药用途 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN118019537A (zh) |
WO (1) | WO2023051606A1 (zh) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110143949A (zh) * | 2018-05-09 | 2019-08-20 | 北京加科思新药研发有限公司 | 可用作shp2抑制剂的新型杂环衍生物 |
WO2020073949A1 (zh) * | 2018-10-10 | 2020-04-16 | 江苏豪森药业集团有限公司 | 含氮杂芳类衍生物调节剂、其制备方法和应用 |
CN112625028A (zh) * | 2015-06-19 | 2021-04-09 | 诺华股份有限公司 | 用于抑制shp2活性的化合物和组合物 |
WO2021197452A1 (zh) * | 2020-04-03 | 2021-10-07 | 上海翰森生物医药科技有限公司 | 含氮杂芳类衍生物自由碱的晶型 |
CN113493440A (zh) * | 2020-04-03 | 2021-10-12 | 上海翰森生物医药科技有限公司 | 含氮杂芳类衍生物的盐及其晶型 |
-
2022
- 2022-09-28 CN CN202280063878.2A patent/CN118019537A/zh active Pending
- 2022-09-28 WO PCT/CN2022/122104 patent/WO2023051606A1/zh unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112625028A (zh) * | 2015-06-19 | 2021-04-09 | 诺华股份有限公司 | 用于抑制shp2活性的化合物和组合物 |
CN110143949A (zh) * | 2018-05-09 | 2019-08-20 | 北京加科思新药研发有限公司 | 可用作shp2抑制剂的新型杂环衍生物 |
WO2020073949A1 (zh) * | 2018-10-10 | 2020-04-16 | 江苏豪森药业集团有限公司 | 含氮杂芳类衍生物调节剂、其制备方法和应用 |
WO2021197452A1 (zh) * | 2020-04-03 | 2021-10-07 | 上海翰森生物医药科技有限公司 | 含氮杂芳类衍生物自由碱的晶型 |
CN113493440A (zh) * | 2020-04-03 | 2021-10-12 | 上海翰森生物医药科技有限公司 | 含氮杂芳类衍生物的盐及其晶型 |
Non-Patent Citations (1)
Title |
---|
XIA LEIMING, YANG FAN, WU XIAO, LI SUZHI, KAN CHEN, ZHENG HONG, WANG SIYING: "SHP2 inhibition enhances the anticancer effect of Osimertinib in EGFR T790M mutant lung adenocarcinoma by blocking CXCL8 loop mediated stemness", CANCER CELL INTERNATIONAL, vol. 21, no. 1, XP093054093, DOI: 10.1186/s12935-021-02056-x * |
Also Published As
Publication number | Publication date |
---|---|
CN118019537A (zh) | 2024-05-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3924053A1 (en) | Pharmaceutical combination comprising tno155 and a krasg12c inhibitor | |
US11666574B2 (en) | Combination therapy involving diaryl macrocyclic compounds | |
TWI762784B (zh) | Cdk4/6抑制劑與egfr抑制劑聯合在製備治療腫瘤疾病的藥物中的用途 | |
KR102418766B1 (ko) | 암 치료에 사용하기 위한 Notch 및 PI3K/mTOR 억제제의 조합 요법 | |
WO2021063332A1 (zh) | 一种ezh2抑制剂与cdk4/6抑制剂联合在制备治疗肿瘤药物中的用途 | |
TWI685341B (zh) | 阿帕替尼和c-Met抑制劑聯合在製備治療腫瘤的藥物中的用途 | |
WO2019109938A1 (zh) | Parp抑制剂用于治疗化疗耐药的卵巢癌或乳腺癌的用途 | |
TW201138764A (en) | Anticancer combinations of artemisinin-based drugs and other chemotherapeutic agents | |
WO2018214925A1 (zh) | 用于治疗结直肠癌的喹啉衍生物 | |
CN115135649A (zh) | 包括吡啶并[1,2-a]嘧啶酮化合物的药物组合 | |
CN111184863B (zh) | 酪氨酸激酶抑制剂、cdk4/6抑制剂、serd联合在制备治疗肿瘤的药物中的用途 | |
Hedayat et al. | Selumetinib: a selective MEK1 inhibitor for solid tumor treatment | |
WO2020239051A1 (zh) | Cdk4/6抑制剂与vegfr抑制剂联合在制备治疗肿瘤的药物中的用途 | |
WO2020177678A1 (zh) | 多靶点酪氨酸激酶抑制剂与egfr抑制剂联合在制备治疗肿瘤的药物中的用途 | |
WO2023051606A1 (zh) | Shp2抑制剂联合egfr-tki治疗和预防肿瘤疾病的医药用途 | |
WO2019220375A1 (en) | Dosing regimens for treatment of solid tumors having one or more genetic alterations in fgfr1, fgfr2, and/or fgfr3 | |
JP7381115B2 (ja) | 組成物及びがん治療用医薬品の調製におけるその応用 | |
JP2022542725A (ja) | 化合物又はその薬学的に許容される塩、二量体又は三量体のがん治療用医薬品の調製における応用 | |
CN115006397A (zh) | 一种预防或治疗肿瘤疾病的药物用途 | |
CN113797342A (zh) | 用于预防或治疗肿瘤疾病的治疗剂组合 | |
WO2022121929A1 (zh) | 吡啶并[1,2-a]嘧啶酮化合物的治疗妇科肿瘤的用途 | |
CN112105361A (zh) | 用于治疗非小细胞肺癌的喹啉衍生物 | |
CN113679720A (zh) | 一种取代丁烯酰胺联合铂类化合物的药物组合物及其用途 | |
NZ786609A (en) | Combination therapy with notch and pi3k/mtor inhibitors for use in treating cancer | |
NZ786604A (en) | Combination therapy with notch and cdk4/6 inhibitors for the treatment of |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22874990 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |