CN115192717B - 一种治疗癌症的药物组合物及其用途 - Google Patents
一种治疗癌症的药物组合物及其用途 Download PDFInfo
- Publication number
- CN115192717B CN115192717B CN202210364948.XA CN202210364948A CN115192717B CN 115192717 B CN115192717 B CN 115192717B CN 202210364948 A CN202210364948 A CN 202210364948A CN 115192717 B CN115192717 B CN 115192717B
- Authority
- CN
- China
- Prior art keywords
- inhibitor
- salt
- fak
- pi3k
- compound
- 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
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 72
- 201000011510 cancer Diseases 0.000 title claims abstract description 34
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 19
- 239000012828 PI3K inhibitor Substances 0.000 claims abstract description 107
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 claims abstract description 107
- 229940124783 FAK inhibitor Drugs 0.000 claims abstract description 106
- 239000003814 drug Substances 0.000 claims abstract description 37
- 150000003839 salts Chemical class 0.000 claims description 86
- 229960003445 idelalisib Drugs 0.000 claims description 68
- 229950004949 duvelisib Drugs 0.000 claims description 65
- YKLIKGKUANLGSB-HNNXBMFYSA-N idelalisib Chemical group C1([C@@H](NC=2[C]3N=CN=C3N=CN=2)CC)=NC2=CC=CC(F)=C2C(=O)N1C1=CC=CC=C1 YKLIKGKUANLGSB-HNNXBMFYSA-N 0.000 claims description 65
- SJVQHLPISAIATJ-ZDUSSCGKSA-N 8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6-ylamino)ethyl]-1-isoquinolinone Chemical group C1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)=CC2=CC=CC(Cl)=C2C(=O)N1C1=CC=CC=C1 SJVQHLPISAIATJ-ZDUSSCGKSA-N 0.000 claims description 61
- 229950008937 defactinib Drugs 0.000 claims description 61
- FWLMVFUGMHIOAA-UHFFFAOYSA-N n-methyl-4-[[4-[[3-[methyl(methylsulfonyl)amino]pyrazin-2-yl]methylamino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide Chemical group C1=CC(C(=O)NC)=CC=C1NC1=NC=C(C(F)(F)F)C(NCC=2C(=NC=CN=2)N(C)S(C)(=O)=O)=N1 FWLMVFUGMHIOAA-UHFFFAOYSA-N 0.000 claims description 61
- 229950002550 copanlisib Drugs 0.000 claims description 38
- PZBCKZWLPGJMAO-UHFFFAOYSA-N copanlisib Chemical group C1=CC=2C3=NCCN3C(NC(=O)C=3C=NC(N)=NC=3)=NC=2C(OC)=C1OCCCN1CCOCC1 PZBCKZWLPGJMAO-UHFFFAOYSA-N 0.000 claims description 36
- 229950010482 alpelisib Drugs 0.000 claims description 32
- 150000001875 compounds Chemical class 0.000 claims description 32
- STUWGJZDJHPWGZ-LBPRGKRZSA-N (2S)-N1-[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)-4-pyridinyl]-2-thiazolyl]pyrrolidine-1,2-dicarboxamide Chemical group S1C(C=2C=C(N=CC=2)C(C)(C)C(F)(F)F)=C(C)N=C1NC(=O)N1CCC[C@H]1C(N)=O STUWGJZDJHPWGZ-LBPRGKRZSA-N 0.000 claims description 30
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 6
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 6
- 201000004101 esophageal cancer Diseases 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000003712 anti-aging effect Effects 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 22
- 230000000694 effects Effects 0.000 abstract description 11
- 230000005764 inhibitory process Effects 0.000 abstract description 7
- 206010059866 Drug resistance Diseases 0.000 abstract description 6
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 50
- 229940125846 compound 25 Drugs 0.000 description 50
- 239000000651 prodrug Substances 0.000 description 50
- 229940002612 prodrug Drugs 0.000 description 50
- 239000012453 solvate Substances 0.000 description 50
- 230000003287 optical effect Effects 0.000 description 49
- 210000004027 cell Anatomy 0.000 description 25
- 206010061534 Oesophageal squamous cell carcinoma Diseases 0.000 description 12
- 208000036765 Squamous cell carcinoma of the esophagus Diseases 0.000 description 12
- 208000007276 esophageal squamous cell carcinoma Diseases 0.000 description 12
- 201000001441 melanoma Diseases 0.000 description 12
- 230000004083 survival effect Effects 0.000 description 12
- 206010041823 squamous cell carcinoma Diseases 0.000 description 11
- 206010060862 Prostate cancer Diseases 0.000 description 10
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 10
- 230000012010 growth Effects 0.000 description 10
- 230000002195 synergetic effect Effects 0.000 description 10
- 206010006187 Breast cancer Diseases 0.000 description 8
- 208000026310 Breast neoplasm Diseases 0.000 description 8
- 208000009956 adenocarcinoma Diseases 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 206010061289 metastatic neoplasm Diseases 0.000 description 8
- 230000005012 migration Effects 0.000 description 8
- 238000013508 migration Methods 0.000 description 8
- 230000012292 cell migration Effects 0.000 description 7
- 238000011534 incubation Methods 0.000 description 7
- CWHUFRVAEUJCEF-UHFFFAOYSA-N BKM120 Chemical compound C1=NC(N)=CC(C(F)(F)F)=C1C1=CC(N2CCOCC2)=NC(N2CCOCC2)=N1 CWHUFRVAEUJCEF-UHFFFAOYSA-N 0.000 description 6
- 206010009944 Colon cancer Diseases 0.000 description 6
- 206010027406 Mesothelioma Diseases 0.000 description 6
- 206010033128 Ovarian cancer Diseases 0.000 description 6
- 206010061535 Ovarian neoplasm Diseases 0.000 description 6
- 239000012980 RPMI-1640 medium Substances 0.000 description 6
- 229950003628 buparlisib Drugs 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 230000035755 proliferation Effects 0.000 description 6
- 239000006143 cell culture medium Substances 0.000 description 5
- 208000003174 Brain Neoplasms Diseases 0.000 description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 4
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 4
- 208000008839 Kidney Neoplasms Diseases 0.000 description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- 206010025323 Lymphomas Diseases 0.000 description 4
- 230000003698 anagen phase Effects 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 208000005017 glioblastoma Diseases 0.000 description 4
- 208000032839 leukemia Diseases 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- 206010027191 meningioma Diseases 0.000 description 4
- 230000001394 metastastic effect Effects 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 208000007538 neurilemmoma Diseases 0.000 description 4
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 206010039667 schwannoma Diseases 0.000 description 4
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 4
- LAJAFFLJAJMYLK-CVOKMOJFSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[[(7s)-4-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5h-benzo[7]annulen-3-yl]amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound N1([C@H]2CCC3=CC=C(C(=C3CC2)OC)NC=2N=C(C(=CN=2)Cl)N[C@H]2[C@H]([C@@]3([H])C[C@@]2(C=C3)[H])C(N)=O)CCOCC1 LAJAFFLJAJMYLK-CVOKMOJFSA-N 0.000 description 3
- SGEUNORSOZVTOL-CABZTGNLSA-N (2S)-2-[[2-[(4S)-4-(difluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]propanamide Chemical compound FC([C@H]1N(C(OC1)=O)C=1N=C2N(CCOC3=C2C=CC(=C3)N[C@H](C(=O)N)C)C=1)F SGEUNORSOZVTOL-CABZTGNLSA-N 0.000 description 3
- IUVCFHHAEHNCFT-INIZCTEOSA-N 2-[(1s)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one Chemical compound C1=C(F)C(OC(C)C)=CC=C1C(C1=C(N)N=CN=C11)=NN1[C@@H](C)C1=C(C=2C=C(F)C=CC=2)C(=O)C2=CC(F)=CC=C2O1 IUVCFHHAEHNCFT-INIZCTEOSA-N 0.000 description 3
- UYJNQQDJUOUFQJ-UHFFFAOYSA-N 2-[[5-chloro-2-[2-methoxy-4-(4-morpholinyl)anilino]-4-pyrimidinyl]amino]-N-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=NC(NC=2C(=CC(=CC=2)N2CCOCC2)OC)=NC=C1Cl UYJNQQDJUOUFQJ-UHFFFAOYSA-N 0.000 description 3
- BCSHRERPHLTPEE-NRFANRHFSA-N 2-[[5-chloro-2-[[(6s)-6-[4-(2-hydroxyethyl)piperazin-1-yl]-1-methoxy-6,7,8,9-tetrahydro-5h-benzo[7]annulen-2-yl]amino]pyrimidin-4-yl]amino]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=NC(NC=2C(=C3CCC[C@@H](CC3=CC=2)N2CCN(CCO)CC2)OC)=NC=C1Cl BCSHRERPHLTPEE-NRFANRHFSA-N 0.000 description 3
- RGHYDLZMTYDBDT-UHFFFAOYSA-N 2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)-7-pyrido[2,3-d]pyrimidinone Chemical compound O=C1N(CC)C2=NC(N)=NC(C)=C2C=C1C=1C=CNN=1 RGHYDLZMTYDBDT-UHFFFAOYSA-N 0.000 description 3
- XUMALORDVCFWKV-IBGZPJMESA-N 2-amino-N-[(1S)-1-[8-[2-(1-methylpyrazol-4-yl)ethynyl]-1-oxo-2-phenylisoquinolin-3-yl]ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C[C@H](NC(=O)C1=C2N=CC=CN2N=C1N)C1=CC2=CC=CC(C#CC3=CN(C)N=C3)=C2C(=O)N1C1=CC=CC=C1 XUMALORDVCFWKV-IBGZPJMESA-N 0.000 description 3
- QINPEPAQOBZPOF-UHFFFAOYSA-N 2-amino-n-[3-[[3-(2-chloro-5-methoxyanilino)quinoxalin-2-yl]sulfamoyl]phenyl]-2-methylpropanamide Chemical compound COC1=CC=C(Cl)C(NC=2C(=NC3=CC=CC=C3N=2)NS(=O)(=O)C=2C=C(NC(=O)C(C)(C)N)C=CC=2)=C1 QINPEPAQOBZPOF-UHFFFAOYSA-N 0.000 description 3
- BEUQXVWXFDOSAQ-UHFFFAOYSA-N 2-methyl-2-[4-[2-(5-methyl-2-propan-2-yl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]propanamide Chemical compound CC(C)N1N=C(C)N=C1C1=CN(CCOC=2C3=CC=C(C=2)C2=CN(N=C2)C(C)(C)C(N)=O)C3=N1 BEUQXVWXFDOSAQ-UHFFFAOYSA-N 0.000 description 3
- LGWACEZVCMBSKW-UHFFFAOYSA-N 5-(6,6-dimethyl-4-morpholin-4-yl-8,9-dihydropurino[8,9-c][1,4]oxazin-2-yl)pyrimidin-2-amine Chemical compound CC1(C)OCCN(C2=N3)C1=NC2=C(N1CCOCC1)N=C3C1=CN=C(N)N=C1 LGWACEZVCMBSKW-UHFFFAOYSA-N 0.000 description 3
- LMJFJIDLEAWOQJ-CQSZACIVSA-N 8-[(1r)-1-(3,5-difluoroanilino)ethyl]-n,n-dimethyl-2-morpholin-4-yl-4-oxochromene-6-carboxamide Chemical compound N([C@H](C)C=1C2=C(C(C=C(O2)N2CCOCC2)=O)C=C(C=1)C(=O)N(C)C)C1=CC(F)=CC(F)=C1 LMJFJIDLEAWOQJ-CQSZACIVSA-N 0.000 description 3
- QIUASFSNWYMDFS-NILGECQDSA-N PX-866 Chemical compound CC(=O)O[C@@H]1C[C@]2(C)C(=O)CC[C@H]2C2=C1[C@@]1(C)[C@@H](COC)OC(=O)\C(=C\N(CC=C)CC=C)C1=C(O)C2=O QIUASFSNWYMDFS-NILGECQDSA-N 0.000 description 3
- 229950006418 dactolisib Drugs 0.000 description 3
- JOGKUKXHTYWRGZ-UHFFFAOYSA-N dactolisib Chemical compound O=C1N(C)C2=CN=C3C=CC(C=4C=C5C=CC=CC5=NC=4)=CC3=C2N1C1=CC=C(C(C)(C)C#N)C=C1 JOGKUKXHTYWRGZ-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- JOWXJLIFIIOYMS-UHFFFAOYSA-N n-hydroxy-2-[[2-(6-methoxypyridin-3-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl-methylamino]pyrimidine-5-carboxamide Chemical compound C1=NC(OC)=CC=C1C1=NC(N2CCOCC2)=C(SC(CN(C)C=2N=CC(=CN=2)C(=O)NO)=C2)C2=N1 JOWXJLIFIIOYMS-UHFFFAOYSA-N 0.000 description 3
- 229940016672 paxalisib Drugs 0.000 description 3
- 229950010632 perifosine Drugs 0.000 description 3
- SZFPYBIJACMNJV-UHFFFAOYSA-N perifosine Chemical compound CCCCCCCCCCCCCCCCCCOP([O-])(=O)OC1CC[N+](C)(C)CC1 SZFPYBIJACMNJV-UHFFFAOYSA-N 0.000 description 3
- 229950005769 pilaralisib Drugs 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- BLGWHBSBBJNKJO-UHFFFAOYSA-N serabelisib Chemical compound C=1C=C2OC(N)=NC2=CC=1C(=CN12)C=CC1=NC=C2C(=O)N1CCOCC1 BLGWHBSBBJNKJO-UHFFFAOYSA-N 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 229950001269 taselisib Drugs 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 229940121344 umbralisib Drugs 0.000 description 3
- 229950001576 voxtalisib Drugs 0.000 description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 206010003571 Astrocytoma Diseases 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 2
- 206010014967 Ependymoma Diseases 0.000 description 2
- 108010067715 Focal Adhesion Protein-Tyrosine Kinases Proteins 0.000 description 2
- 102000016621 Focal Adhesion Protein-Tyrosine Kinases Human genes 0.000 description 2
- 102100039788 GTPase NRas Human genes 0.000 description 2
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 2
- 206010066476 Haematological malignancy Diseases 0.000 description 2
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 2
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 2
- 208000000172 Medulloblastoma Diseases 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 201000004404 Neurofibroma Diseases 0.000 description 2
- 208000005890 Neuroma Diseases 0.000 description 2
- 201000010133 Oligodendroglioma Diseases 0.000 description 2
- 102000038030 PI3Ks Human genes 0.000 description 2
- 108091007960 PI3Ks Proteins 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 208000007641 Pinealoma Diseases 0.000 description 2
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- 206010041067 Small cell lung cancer Diseases 0.000 description 2
- 206010068771 Soft tissue neoplasm Diseases 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 206010043189 Telangiectasia Diseases 0.000 description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- 208000008385 Urogenital Neoplasms Diseases 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 208000002517 adenoid cystic carcinoma Diseases 0.000 description 2
- 208000037844 advanced solid tumor Diseases 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 201000007983 brain glioma Diseases 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 208000030381 cutaneous melanoma Diseases 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 208000014616 embryonal neoplasm Diseases 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 201000005649 gangliocytoma Diseases 0.000 description 2
- 201000008361 ganglioneuroma Diseases 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 208000006178 malignant mesothelioma Diseases 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 201000005282 malignant pleural mesothelioma Diseases 0.000 description 2
- 208000037843 metastatic solid tumor Diseases 0.000 description 2
- 208000025189 neoplasm of testis Diseases 0.000 description 2
- 206010061311 nervous system neoplasm Diseases 0.000 description 2
- 208000027831 neuroepithelial neoplasm Diseases 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 208000024724 pineal body neoplasm Diseases 0.000 description 2
- 208000010916 pituitary tumor Diseases 0.000 description 2
- 201000003437 pleural cancer Diseases 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 201000007416 salivary gland adenoid cystic carcinoma Diseases 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 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 2
- 201000003708 skin melanoma Diseases 0.000 description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- 208000009056 telangiectasis Diseases 0.000 description 2
- 201000003120 testicular cancer Diseases 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- 210000002229 urogenital system Anatomy 0.000 description 2
- 208000022671 urothelial neoplasm Diseases 0.000 description 2
- 210000003741 urothelium Anatomy 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 101710167800 Capsid assembly scaffolding protein Proteins 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 1
- 101710130420 Probable capsid assembly scaffolding protein Proteins 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 241001591024 Samea Species 0.000 description 1
- 101710204410 Scaffold protein Proteins 0.000 description 1
- 229940100514 Syk tyrosine kinase inhibitor Drugs 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009044 synergistic interaction Effects 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- 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
-
- 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
- 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
- A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
-
- 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种治疗癌症的药物组合物及其用途,属于医药领域。该药物组合物由FAK抑制剂和PI3K抑制剂组成。本发明还提供了FAK抑制剂和PI3K抑制剂联合用药治疗癌症。本发明PI3K抑制剂和FAK抑制剂联合用药,能够发挥协同增效的作用,显著提高对肿瘤的抑制效果,并克服肿瘤耐药性,为临床治疗癌症提供了良好的选择。
Description
技术领域
本发明属于医药领域,具体涉及一种治疗癌症的药物组合物及其用途。
背景技术
癌症通常泛指所有恶性肿瘤,具有细胞分化和增殖异常、生长失去控制、浸润性和转移性等生物学特征。每年因为各种癌症死亡人数很多,严重威胁人类的生存。目前肿瘤的临床治疗依然以手术、化疗药物为主,但进入二十一世纪以来分子靶向药物治疗正扮演着越来越重要的角色。分子靶向药物相较于传统的细胞毒性药物,因为以肿瘤细胞不同于正常细胞的特征为靶点,由盲目攻击变为有的放矢,在发挥强大的抗肿瘤作用同时,减少了对正常器官和组织的毒副作用,从而改善患者生存质量,因此成为肿瘤治疗药物研发的热点。
磷脂酰肌醇3-激酶(PI3K)是PI3K/AKT/mTOR信号通路的起始节点,在肿瘤细胞的增殖、迁移、侵袭、血管生成等过程中起重要作用,成为肿瘤靶向治疗的热门靶点。PI3K抑制剂有望用于治疗癌症。但是,研究发现,PI3K抑制剂单独用药的抗肿瘤效果并不是很好,且毒副作用较大。
局部黏着斑激酶(focal adhesion kinase,FAK)是一种非受体型酪氨酸蛋白激酶,是细胞内重要的骨架蛋白与多种信号通路的关键分子。FAK在肿瘤发生、发展、迁移和侵袭的各个阶段都具有重要作用。目前,FAK被当作潜在的肿瘤治疗靶点,FAK抑制剂作为配体,可与ATP竞争性结合FAK受体的结合位点,阻断FAK介导的生长、增殖信号通路的信息传递,导致恶性肿瘤细胞生长增殖受抑制,甚至在大剂量时导致细胞死亡。但是FAK抑制剂同样存在毒副作用大的问题。而且,随着研究深入,还发现FAK在癌症病情发展中所起的生物学作用是复杂的,其治疗癌症效果并不能确定。
并且,在治疗癌症过程中,耐药性问题一直是一个很大的困扰。如何克服癌细胞耐药性,也是癌症治疗研究的一个难点。目前尚未见将PI3K抑制剂和FAK抑制剂联合使用制备治疗癌症的药物,其是否具有治疗癌症的效果,是否可以克服癌细胞耐药性都有待进一步研究。
发明内容
本发明的目的是提供一种治疗癌症的药物组合物及其用途。
本发明提供了一种治疗癌症的药物组合物,它由FAK抑制剂和PI3K抑制剂组成。
进一步地,所述FAK抑制剂和PI3K抑制剂的重量比为1:10~10:1。
进一步地,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:Defactinib、CEP-28122、CEP-37440、TAE226、PF-562271、PF-431396、VS-4718、PF-573228、BI853520、IN10018;
或者,所述FAK抑制剂为式I所示化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:
其中,R1、R2分别独立选自氢、甲基、三氘代甲基;
或者,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:
;
优选地,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:或Defactinib。
进一步地,所述PI3K抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:Alpelisib、GDC-0077、TAK-117、AZD-8186、IPI-549、Idelalisib、Buparlisib、Pilaralisib、Copanlisib、PX-866、Paxalisib、Duvelisib、Umbralisib、Taselisib、Perifosine、Buparlisib、Dactolisib、CUDC-907、Voxtalisib;
优选地,所述PI3K抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:Alpelisib、Copanlisib、Duvelisib或Idelalisib。
进一步地,所述FAK抑制剂和PI3K抑制剂的摩尔比为1:60.06~8.13:1。
进一步地,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:
所述PI3K抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:Copanlisib、Duvelisib或Idelalisib;
所述FAK抑制剂和PI3K抑制剂的摩尔比为1:60.06~8.13:1;
或者,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:Defactinib;
所述PI3K抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:Alpelisib、Duvelisib或Idelalisib;
所述FAK抑制剂和PI3K抑制剂的摩尔比为1:10~1:2。
进一步地,所述FAK抑制剂为化合物或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述PI3K抑制剂为Copanlisib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和PI3K抑制剂的摩尔比为2.7:1或8.13:1;
或者,所述FAK抑制剂为化合物或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述PI3K抑制剂为Duvelisib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:60.06或1:20.02;
或者,所述FAK抑制剂为化合物或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述PI3K抑制剂为Idelalisib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:60.06或1:20.02;
或者,所述FAK抑制剂为Defactinib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:所述PI3K抑制剂为Alpelisib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:2或1:6;
或者,所述FAK抑制剂为Defactinib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:所述PI3K抑制剂为Duvelisib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:3.33或1:10;
或者,所述FAK抑制剂为Defactinib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:所述PI3K抑制剂为Idelalisib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:6.67。
本发明还提供了一种前述的药物组合物的制备方法,它包括如下步骤:按照重量比取FAK抑制剂和PI3K抑制剂,混合,即可。
本发明还提供了前述的药物组合物在制备治疗癌症的药物中的用途;
优选地,所述癌症为实体瘤、间皮瘤、黑素瘤、前列腺癌、乳腺癌、胶质母细胞瘤、脑癌、食管癌;
所述实体瘤包括间皮瘤、胰腺癌、软组织肿瘤、转移瘤、非固体癌、肉瘤、腺癌、肺癌、乳腺癌、淋巴瘤、胃肠道癌、泌尿生殖系统癌、前列腺癌、卵巢癌;所述胃肠道癌包括结肠癌、所述泌尿生殖系统癌包括肾、尿路上皮或睾丸肿瘤;所述卵巢癌包括晚期卵巢癌;
所述间皮瘤包括神经纤维瘤、肾癌、肺癌、小细胞肺癌、非小细胞肺癌、KRAS突变体非小细胞肺癌、肝癌、甲状腺癌、乳腺癌、神经系统肿瘤、神经鞘瘤、脑膜瘤、神经瘤、腺样囊性癌、室管膜瘤、室管膜肿瘤、恶性胸膜瘤、恶性胸膜间皮瘤、三联体瘤、阴性乳腺癌、非血液恶性肿瘤、黑素瘤、结直肠癌、白血病、腺癌、固体肿瘤;
所述黑素瘤包括局部晚期黑素瘤、局部突变的N-Ras引起的黑素瘤、转移性恶性皮肤黑色素瘤;所述结直肠癌包括转移性结直肠癌;所述白血病包括急性髓性白血病;所述腺癌包括腺癌;所述固体肿瘤包括局部晚期实体瘤、转移性实体瘤、肝细胞癌;
所述前列腺癌包括去势抵抗性前列腺癌、转移性去势抵抗性前列腺癌;
所述脑癌包括神经上皮组织肿瘤、脑胶质瘤、星形细胞瘤、少突胶质瘤、室管膜与脉络丛肿瘤、松果体肿瘤、神经细胞肿瘤、神经节细胞瘤、神经母细胞瘤、分化不良的肿瘤、胚胎性肿瘤、多形胶质母细胞瘤、髓母细胞瘤、神经鞘膜瘤、脑膜瘤、恶性淋巴癌、脑血管肿瘤、畸形性胛溜、腕咽賫瘤,血管畸形毛细血管扩张、垂体肿瘤、转移性肿瘤;
所述食管癌为食管鳞癌。
本发明还提供了一种治疗癌症的药物制剂,它是由前述的药物组合物为活性成分,加上药学上可接受的辅料或者辅助性成分制备而成的制剂。
本发明还提供了一种治疗癌症的联合用药物,它含有相同或者不同规格的同时或者分别给药的FAK抑制剂和PI3K抑制剂,以及药学上可接受的载体;
优选地,所述FAK抑制剂和PI3K抑制剂的重量比为1:10~10:1;
更优选地,所述FAK抑制剂和PI3K抑制剂的摩尔比为1:60.06~8.13:1。
进一步地,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:Defactinib、CEP-28122、CEP-37440、TAE226、PF-562271、PF-431396、VS-4718、PF-573228、BI853520、IN10018;
或者,所述FAK抑制剂为式I所示化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:
其中,R1、R2分别独立选自氢、甲基、三氘代甲基;
或者,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:
;
优选地,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:或Defactinib。
进一步地,所述PI3K抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:Alpelisib、GDC-0077、TAK-117、AZD-8186、IPI-549、Idelalisib、Buparlisib、Pilaralisib、Copanlisib、PX-866、Paxalisib、Duvelisib、Umbralisib、Taselisib、Perifosine、Buparlisib、Dactolisib、CUDC-907、Voxtalisib;
优选地,所述PI3K抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:Alpelisib、Copanlisib、Duvelisib或Idelalisib。
本发明还提供了FAK抑制剂和PI3K抑制剂联用在制备治疗癌症的药物中的用途;
优选地,所述FAK抑制剂和PI3K抑制剂的重量比为1:10~10:1。
进一步地,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:Defactinib、CEP-28122、CEP-37440、TAE226、PF-562271、PF-431396、VS-4718、PF-573228、BI853520、IN10018;
或者,所述FAK抑制剂为式I所示化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:
其中,R1、R2分别独立选自氢、甲基、三氘代甲基;
或者,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:
;
优选地,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:或Defactinib。
进一步地,所述PI3K抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:Alpelisib、GDC-0077、TAK-117、AZD-8186、IPI-549、Idelalisib、Buparlisib、Pilaralisib、Copanlisib、PX-866、Paxalisib、Duvelisib、Umbralisib、Taselisib、Perifosine、Buparlisib、Dactolisib、CUDC-907、Voxtalisib;
优选地,所述PI3K抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:Alpelisib、Copanlisib、Duvelisib或Idelalisib。
进一步地,所述FAK抑制剂和PI3K抑制剂的摩尔比为1:60.06~8.13:1;
优选地,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:
所述PI3K抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:Copanlisib、Duvelisib或Idelalisib;
所述FAK抑制剂和PI3K抑制剂的摩尔比为1:60.06~8.13:1;
或者,所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:Defactinib;
所述PI3K抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:Alpelisib、Duvelisib或Idelalisib;
所述FAK抑制剂和PI3K抑制剂的摩尔比为1:10~1:2。
进一步地,所述FAK抑制剂为化合物或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述PI3K抑制剂为Copanlisib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和PI3K抑制剂的摩尔比为2.7:1或8.13:1;
或者,所述FAK抑制剂为化合物或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述PI3K抑制剂为Duvelisib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:60.06或1:20.02;
或者,所述FAK抑制剂为化合物或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述PI3K抑制剂为Idelalisib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:60.06或1:20.02;
或者,所述FAK抑制剂为Defactinib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:所述PI3K抑制剂为Alpelisib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:2或1:6;
或者,所述FAK抑制剂为Defactinib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:所述PI3K抑制剂为Duvelisib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:3.33或1:10;
或者,所述FAK抑制剂为Defactinib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物:所述PI3K抑制剂为Idelalisib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:6.67。
进一步地,所述癌症为实体瘤、间皮瘤、黑素瘤、前列腺癌、乳腺癌、胶质母细胞瘤、脑癌、食管癌;
所述实体瘤包括间皮瘤、胰腺癌、软组织肿瘤、转移瘤、非固体癌、肉瘤、腺癌、肺癌、乳腺癌、淋巴瘤、胃肠道癌、泌尿生殖系统癌、前列腺癌、卵巢癌;所述胃肠道癌包括结肠癌、所述泌尿生殖系统癌包括肾、尿路上皮或睾丸肿瘤;所述卵巢癌包括晚期卵巢癌;
所述间皮瘤包括神经纤维瘤、肾癌、肺癌、小细胞肺癌、非小细胞肺癌、KRAS突变体非小细胞肺癌、肝癌、甲状腺癌、乳腺癌、神经系统肿瘤、神经鞘瘤、脑膜瘤、神经瘤、腺样囊性癌、室管膜瘤、室管膜肿瘤、恶性胸膜瘤、恶性胸膜间皮瘤、三联体瘤、阴性乳腺癌、非血液恶性肿瘤、黑素瘤、结直肠癌、白血病、腺癌、固体肿瘤;
所述黑素瘤包括局部晚期黑素瘤、局部突变的N-Ras引起的黑素瘤、转移性恶性皮肤黑色素瘤;所述结直肠癌包括转移性结直肠癌;所述白血病包括急性髓性白血病;所述腺癌包括腺癌;所述固体肿瘤包括局部晚期实体瘤、转移性实体瘤、肝细胞癌;
所述前列腺癌包括去势抵抗性前列腺癌、转移性去势抵抗性前列腺癌;
所述脑癌包括神经上皮组织肿瘤、脑胶质瘤、星形细胞瘤、少突胶质瘤、室管膜与脉络丛肿瘤、松果体肿瘤、神经细胞肿瘤、神经节细胞瘤、神经母细胞瘤、分化不良的肿瘤、胚胎性肿瘤、多形胶质母细胞瘤、髓母细胞瘤、神经鞘膜瘤、脑膜瘤、恶性淋巴癌、脑血管肿瘤、畸形性胛溜、腕咽賫瘤,血管畸形毛细血管扩张、垂体肿瘤、转移性肿瘤;
所述食管癌为食管鳞癌。
本发明PI3K抑制剂和FAK抑制剂联合用药,能够发挥协同增效的作用,显著提高对肿瘤的抑制效果,并克服肿瘤耐药性,为临床治疗癌症提供了良好的选择。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为化合物25(3.33μM)-Copanlisib(1.23μM)联用生存率柱状图。
图2为化合物25(10μM)-Copanlisib(1.23μM)联用生存率柱状图。
图3为化合物25(1.11μM)-Duvelisib(66.67μM)联用生存率柱状图。
图4为化合物25(3.33μM)-Duvelisib(66.67μM)联用生存率柱状图。
图5为化合物25(1.11μM)-Idelalisib(66.67μM)联用生存率柱状图。
图6为化合物25(3.33μM)-Idelalisib(66.67μM)联用生存率柱状图。
图7为化合物25与Copanlisib、Duvelisib或Idelalisib联用迁移面积柱状图。
图8为化合物25与Copanlisib、Duvelisib或Idelalisib联用划痕迁移面积图。
图9为Defactinib(3.333μM)-Alpelisib(6.667μM)联用生存率柱状图。
图10为Defactinib(3.333μM)-Alpelisib(20μM)联用生存率柱状图。
图11为Defactinib(3.333μM)-Duvelisib(11.11μM)联用生存率柱状图。
图12为Defactinib(3.333μM)-Duvelisib(33.33μM)联用生存率柱状图。
图13为Defactinib(10μM)-Idelalisib(66.67μM)联用生存率柱状图。
图14为Defactinib与Alpelisib、Duvelisib或Idelalisib联用迁移面积柱状图。
图15为Defactinib与Alpelisib、Duvelisib或Idelalisib联用划痕迁移面积图。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
本发明实施例中,化合物25结构为按照申请号为201910373081.2的专利所述方法制备。Alpelisib、Copanlisib、Duvelisib以及Idelalisib为市售PI3K抑制剂。Defactinib为市售FAK抑制剂。
实施例1、本发明药物组合物抑制癌症细胞增殖的效果
1、实验方法
取处于对数生长期的食管鳞癌EC109细胞,以1.5×103个/孔的浓度接种于96孔培养板中。并于37℃,5%的CO2浓度及饱和湿度条件的培养箱中孵育48小时。阴性对照孔加入和药物同体积的含10%胎牛血清的RPMI 1640细胞培养液。孵育48小时后,将药物FAK抑制剂(化合物25)和PI3K抑制剂(Copanlisib、Duvelisib或Idelalisib)先后加入96孔板。
化合物25的浓度为:0μM、0.002μM、0.005μM、0.014μM、0.041μM、0.123μM、0.370μM、1.111μM、3.333μM或10μM。
Copanlisib的浓度为:0μM、1.23μM、3.70μM、11.11μM、33.33μM或100μM。
Duvelisib的浓度为:0μM、2.47μM、7.41μM、22.22μM、66.67μM或200μM。
Idelalisib浓度范围为:0μM、2.47μM、7.41μM、22.22μM、66.67μM或200μM。
加入药物共孵育3天后,每孔加入10μL CCK-8,继续培养4小时。于酶标仪中按照波长450nm进行各孔吸光度值(OD)测定。按公式计算细胞生长抑制率。抑制率(%)=(1-加药孔OD值/对照孔OD值)×100%。再按照Combination index(CI)药物联合指数进行判定。CI值判定标准如表1所示:
表1.CI值判定标准
2、实验结果
(1)、化合物25和Copanlisib联合用药(化合物25&Copanlisib)
化合物25和Copanlisib联合用药结果如图1~2所示。由图1~2可知:当化合物25和Copanlisib的摩尔比为2.7:1或8.13:1时,化合物25和Copanlisib联合用药对于抑制EC109细胞生长有协同增效作用,可用于协同增效治疗食管鳞癌。
(2)、化合物25和Duvelisib联合用药(化合物25&Duvelisib)
化合物25和Duvelisib联合用药结果如图2~4所示。由图2~4可知:当化合物25和Duvelisib的摩尔比为1:60.06或1:20.02时,化合物25和Duvelisib联合用药对于抑制EC109细胞生长有协同增效作用,可用于协同增效治疗食管鳞癌。
(3)、化合物25和Idelalisib联合用药(化合物25&Idelalisib)
化合物25和Idelalisib联合用药结果如图5~6所示。由图5~6可知:当化合物25和Idelalisib的摩尔比为1:60.06或1:20.02时,化合物25和Idelalisib联合用药对于抑制EC109细胞生长有协同增效作用,可用于协同增效治疗食管鳞癌。
上述实施例提供了一种治疗食管鳞癌的联合用药物,实验结果说明化合物25与PI3K抑制剂(Copanlisib、Duvelisib或Idelalisib)联合用药均具有协同增效作用,可以显著抑制食管鳞癌细胞的生长增殖,其抗癌效果明显优于化合物25、PI3K抑制剂(Copanlisib、Duvelisib或Idelalisib)单独使用,本发明的联合用药物在食管鳞癌的治疗领域具有很好的临床应用前景。
实施例2、本发明药物组合物抑制癌症细胞迁移的效果
1、实验方法
取处于对数生长期的食管鳞癌EC109细胞,以1.0×106个/孔的浓度接种于6孔培养板中。并于37℃,5%的CO2浓度及饱和湿度条件的培养箱中孵育24小时。将6孔板中的细胞进行划痕,每孔3道划痕,划痕后吸弃培养基再用PBS漂洗一遍除去漂浮细胞。阴性对照孔加入和药物同体积的无血清的RPMI 1640细胞培养液(含20ng/ml HGF)。药物均使用含20ng/ml HGF的无血清RPMI 1640细胞培养液进行配制。将化合物25和PI3K抑制剂(Copanlisib、Duvelisib或Idelalisib)先后加入6孔板。
化合物25浓度为:0.2044μM;
Copanlisib浓度为:0.04μM;
Duvelisib浓度为:0.746μM;
Idelalisib浓度为:1.672μM。
单独加入4种药物(化合物25、Copanlisib、Duvelisib或Idelalisib),或者同时加入化合物25和Copanlisib(化合物25&Copanlisib,化合物25浓度为0.2044μM,Copanlisib浓度为0.04μM)、或者同时加入化合物25和Duvelisib(化合物25&Duvelisib,化合物25浓度为0.2044μM,Duvelisib浓度为0.746μM)、或者同时加入化合物25和Idelalisib(化合物25&Idelalisib,化合物25浓度为0.2044μM,Idelalisib浓度为1.672μM),孵育2天后,吸弃培养基,用PBS漂洗一遍除去漂浮细胞,于显微镜下观察细胞迁移情况,并使用放大倍数为目镜10×物镜10×进行拍照(0h及48h均需拍照)。使用Image J进行图片处理分析细胞迁移率。迁移率计算公式:
迁移率(%)=[划痕面积(0h)-划痕面积(48h)]/划痕面积(0h)×100%
使用迁移率通过Prism统计制作柱状图并进行t检验。若p<0.05即有显著差异。
2、实验结果
细胞迁移结果如图7~8和表2所示。
表2.各组细胞迁移结果显著性差异统计结果
药物组合 | P值 |
化合物25&Copanlisib vs化合物25 | 0.0003 |
化合物25&Duvelisib vs化合物25 | 0.0167 |
化合物25&Idelalisib vs化合物25 | <0.0001 |
化合物25&Copanlisib vs Copanlisib | 0.002 |
化合物25&Duvelisib vs Duvelisib | 0.0176 |
化合物25&Idelalisib vs Idelalisib | 0.001 |
由图7~8以及表2可知:化合物25与PI3K抑制剂(Copanlisib、Duvelisib或Idelalisib)联合用药具有协同增效作用,可以显著抑制食管鳞癌细胞的迁移,其抗癌效果明显优于化合物25、PI3K抑制剂(Copanlisib/Duvelisib/Idelalisib)单独使用,本发明的联合用药物在食管鳞癌的治疗领域具有很好的临床应用前景。
实施例3、本发明药物组合物治疗癌症的效果
1、实验方法
取处于对数生长期的食管鳞癌EC109细胞,以1.0×103个/孔的浓度接种于96孔培养板中。并于37℃,5%的CO2浓度及饱和湿度条件的培养箱中孵育48小时。阴性对照孔加入和药物同体积的含10%胎牛血清的RPMI 1640细胞培养液。将药物FAK抑制剂Defactinib和PI3K抑制剂(Alpelisib、Duvelisib或Idelalisib)先后加入96孔板。
Defactinib的浓度为:0μM、0.002μM、0.005μM、0.014μM、0.041μM、0.123μM、0.370μM、1.111μM、3.333μM或10μM。
Alpelisib的浓度为:0μM、0.247μM、0.741μM、2.222μM、6.667μM或20μM。
Duvelisib的浓度为:0μM、1.23μM、3.70μM、11.11μM、33.33μM或100μM。
Idelalisib浓度范围为:0μM、2.47μM、7.41μM、22.22μM、66.67μM或200μM。
加入药物共孵育7天后,每孔加入10μL CCK-8,继续培养4小时。于酶标仪中按照波长450nm进行各孔吸光度值(OD)测定。按公式计算细胞生长抑制率。抑制率(%)=(1-加药孔OD值/对照孔OD值)×100%。再按照Combination index(CI)药物联合指数进行判定。CI值判定标准如表1所示。
2、实验结果
(1)、Defactinib和Alpelisib联合用药(Defactinib&Alpelisib)
Defactinib和Alpelisib联合用药结果如图9~10所示。由图9~10可知:当Defactinib和Alpelisib的摩尔比为1:2或1:6时,Defactinib和Alpelisib联合用药对于抑制EC109细胞生长有协同增效作用,可用于协同增效治疗食管鳞癌。
(2)、Defactinib和Duvelisib联合用药(Defactinib&Duvelisib)
Defactinib和Duvelisib联合用药结果如图11~12所示。由图11~12可知:当Defactinib和Duvelisib的摩尔比为1:3.33或1:10时,Defactinib和Duvelisib联合用药对于抑制EC109细胞生长有协同增效作用,可用于协同增效治疗食管鳞癌。
(3)、Defactinib和Idelalisib联合用药(Defactinib&Idelalisib)
Defactinib和Idelalisib联合用药结果如图13所示。由图13可知:当Defactinib和Idelalisib的摩尔比为1:6.67时,Defactinib和Idelalisib联合用药对于抑制EC109细胞生长有协同增效作用,可用于协同增效治疗食管鳞癌。
综上,本发明提供了一种治疗食管鳞癌的联合用药物,Defactinib与PI3K抑制剂(Alpelisib/Duvelisib/Idelalisib)联合用药均具有协同增效作用,可以显著抑制食管鳞癌细胞的生长增殖,其抗癌效果明显优于Defactinib、PI3K抑制剂(Alpelisib/Duvelisib/Idelalisib)单独使用,本发明的联合用药物在食管鳞癌的治疗领域具有很好的临床应用前景。
实施例4、本发明药物组合物治疗癌症的效果
1、实验方法
取处于对数生长期的食管鳞癌EC109细胞,以5.0×105个/孔的浓度接种于12孔培养板中。并于37℃,5%的CO2浓度及饱和湿度条件的培养箱中孵育24小时。将12孔板中的细胞进行划痕,每孔3道划痕,划痕后吸弃培养基再用PBS漂洗一遍除去漂浮细胞。阴性对照孔加入和药物同体积的无血清的RPMI 1640细胞培养液(含20ng/ml HGF)。药物均使用含20ng/ml HGF的无血清RPMI 1640细胞培养液进行配制,将药物FAK抑制剂Defactinib和PI3K抑制剂(Alpelisib、Duvelisib或Idelalisib)先后加入12孔板。
Defactinib浓度为:0.370μM;
Alpelisib浓度为:0.123μM;
Duvelisib浓度为:0.746μM;
Idelalisib浓度为:1.672μM。
单独加入4种药物(Defactinib、Alpelisib、Duvelisib或Idelalisib),或者同时加入Defactinib和Alpelisib(Defactinib&Alpelisib,Defactinib浓度为0.370μM,Alpelisib浓度为0.123μM)、或者同时加入Defactinib和Duvelisib(Defactinib&Duvelisib,Defactinib浓度为0.370μM,Duvelisib浓度为0.746μM)、或者同时加入Defactinib和Idelalisib(Defactinib&Idelalisib,Defactinib浓度为0.370μM,Idelalisib浓度为1.672μM),孵育2天后,吸弃培养基,用PBS漂洗一遍除去漂浮细胞,于显微镜下观察细胞迁移情况,并使用放大倍数为目镜10×物镜4×进行拍照(0h及48h均需拍照)。使用Image J进行图片处理分析细胞迁移率。迁移率计算公式:
迁移率(%)=[划痕面积(0h)-划痕面积(48h)]/划痕面积(0h)×100%
使用迁移率通过Prism统计制作柱状图并进行t检验。若p<0.05即有显著差异。
2、实验结果
细胞迁移结果如图14~15和表3所示。
表3.各组细胞迁移结果显著性差异统计结果
药物组合 | P值 |
Defactinib&Alpelisib vs Defactinib | 0.0009 |
Defactinib&Duvelisib vs Defactinib | 0.001 |
Defactinib&Idelalisib vs Defactinib | 0.0011 |
Defactinib&Alpelisib vs Alpelisib | 0.0001 |
Defactinib&Duvelisib vs Duvelisib | 0.0011 |
Defactinib&Idelalisib vs Idelalisib | 0.0004 |
由图14~15和表3可知,本发明提供了一种治疗食管鳞癌的联合用药物,Defactinib与PI3K抑制剂(Alpelisib/Duvelisib/Idelalisib)联合用药均具有协同增效作用,可以显著抑制食管鳞癌细胞的迁移,其抗癌效果明显优于Defactinib、PI3K抑制剂(Alpelisib/Duvelisib/Idelalisib)单独使用,本发明的联合用药物在食管鳞癌的治疗领域具有很好的临床应用前景。
综上,本发明研究发现PI3K抑制剂和FAK抑制剂联合用药,能够发挥协同增效的作用,显著提高对肿瘤的抑制效果,并克服肿瘤耐药性,为临床治疗癌症提供了良好的选择。
Claims (6)
1.一种治疗癌症的药物组合物,其特征在于:它是由FAK抑制剂和PI3K抑制剂组成;
所述FAK抑制剂为化合物或其盐;所述PI3K抑制剂为Copanlisib或其盐;所述FAK抑制剂和PI3K抑制剂的摩尔比为2.7:1~8.13:1;
或者,所述FAK抑制剂为化合物或其盐;所述PI3K抑制剂为Duvelisib或其盐;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:60.06~1:20.02;
或者,所述FAK抑制剂为化合物或其盐;所述PI3K抑制剂为Idelalisib或其盐;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:60.06~1:20.02;
或者,所述FAK抑制剂为Defactinib或其盐:所述PI3K抑制剂为Alpelisib或其盐;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:2~1:6;
或者,所述FAK抑制剂为Defactinib或其盐:所述PI3K抑制剂为Duvelisib或其盐;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:3.33~1:10;
或者,所述FAK抑制剂为如下化合物或其盐:Defactinib;所述PI3K抑制剂为如下化合物或其盐:Idelalisib;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:6.67。
2.一种权利要求1所述的药物组合物的制备方法,其特征在于:它包括如下步骤:按照重量比取FAK抑制剂和PI3K抑制剂,混合,即可。
3.权利要求1所述的药物组合物在制备治疗癌症的药物中的用途;
所述癌症为食管癌。
4.一种治疗癌症的药物制剂,其特征在于:它是由权利要求1所述的药物组合物为活性成分,加上药学上可接受的辅料或者辅助性成分制备而成的制剂。
5.一种治疗癌症的联合用药物,其特征在于:它含有相同或者不同规格的同时或者分别给药的FAK抑制剂和PI3K抑制剂,以及药学上可接受的载体;
所述FAK抑制剂为化合物或其盐;所述PI3K抑制剂为Copanlisib或其盐;所述FAK抑制剂和PI3K抑制剂的摩尔比为2.7:1~8.13:1;
或者,所述FAK抑制剂为化合物或其盐;所述PI3K抑制剂为Duvelisib或其盐;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:60.06~1:20.02;
或者,所述FAK抑制剂为化合物或其盐;所述PI3K抑制剂为Idelalisib或其盐;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:60.06~1:20.02;
或者,所述FAK抑制剂为Defactinib或其盐:所述PI3K抑制剂为Alpelisib或其盐;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:2~1:6;
或者,所述FAK抑制剂为Defactinib或其盐:所述PI3K抑制剂为Duvelisib或其盐;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:3.33~1:10;
或者,所述FAK抑制剂为如下化合物或其盐:Defactinib;所述PI3K抑制剂为如下化合物或其盐:Idelalisib;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:6.67。
6.FAK抑制剂和PI3K抑制剂联用在制备治疗癌症的药物中的用途;
所述FAK抑制剂为化合物或其盐;所述PI3K抑制剂为Copanlisib或其盐;所述FAK抑制剂和PI3K抑制剂的摩尔比为2.7:1~8.13:1;
或者,所述FAK抑制剂为化合物或其盐;所述PI3K抑制剂为Duvelisib或其盐;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:60.06~1:20.02;
或者,所述FAK抑制剂为化合物或其盐;所述PI3K抑制剂为Idelalisib或其盐;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:60.06~1:20.02;
或者,所述FAK抑制剂为Defactinib或其盐:所述PI3K抑制剂为Alpelisib或其盐;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:2~1:6;
或者,所述FAK抑制剂为Defactinib或其盐:所述PI3K抑制剂为Duvelisib或其盐;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:3.33~1:10;
或者,所述FAK抑制剂为如下化合物或其盐:Defactinib;所述PI3K抑制剂为如下化合物或其盐:Idelalisib;所述FAK抑制剂和PI3K抑制剂的摩尔比为1:6.67;
所述癌症为食管癌。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2021103780433 | 2021-04-08 | ||
CN202110378043 | 2021-04-08 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115192717A CN115192717A (zh) | 2022-10-18 |
CN115192717B true CN115192717B (zh) | 2023-12-12 |
Family
ID=83574366
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210364948.XA Active CN115192717B (zh) | 2021-04-08 | 2022-04-08 | 一种治疗癌症的药物组合物及其用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115192717B (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103127510A (zh) * | 2011-11-30 | 2013-06-05 | 北京天和瑞通科技发展有限公司 | 含有肝细胞生长因子受体抑制剂和Bcl-2抑制剂的药物组合物及其应用 |
CN111377871A (zh) * | 2018-12-27 | 2020-07-07 | 成都海创药业有限公司 | 一种fak抑制剂及其联合用药物 |
WO2020257615A1 (en) * | 2019-06-21 | 2020-12-24 | Nidhi Singh | Therapeutic compositions and methods for treating cancers |
CN112121048A (zh) * | 2019-06-06 | 2020-12-25 | 正大天晴药业集团股份有限公司 | 用于联合治疗食管癌的喹啉类化合物 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20200316053A1 (en) * | 2018-01-22 | 2020-10-08 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Application of novel tyrosine kinase inhibitor, anlotinib, in osteosarcoma and chondrosarcoma |
-
2022
- 2022-04-08 CN CN202210364948.XA patent/CN115192717B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103127510A (zh) * | 2011-11-30 | 2013-06-05 | 北京天和瑞通科技发展有限公司 | 含有肝细胞生长因子受体抑制剂和Bcl-2抑制剂的药物组合物及其应用 |
CN111377871A (zh) * | 2018-12-27 | 2020-07-07 | 成都海创药业有限公司 | 一种fak抑制剂及其联合用药物 |
CN112121048A (zh) * | 2019-06-06 | 2020-12-25 | 正大天晴药业集团股份有限公司 | 用于联合治疗食管癌的喹啉类化合物 |
WO2020257615A1 (en) * | 2019-06-21 | 2020-12-24 | Nidhi Singh | Therapeutic compositions and methods for treating cancers |
Non-Patent Citations (2)
Title |
---|
Focal adhesion kinase (FAK) inhibitor‐defactinib suppresses the malignant progression of human esophageal squamous cell carcinoma (ESCC) cells via effective blockade of PI3K/AKT axis and downstream molecular network;Lingyuan Zhang,等;《Mol Carcinog》;第60卷(第2期);摘要和第116-123页 * |
Isoform-Selective PI3K Inhibitors for Various Diseases;Rammohan R Y Bheemanaboina;《Curr Top Med Chem.》;第20卷;摘要和第1076-1086页 * |
Also Published As
Publication number | Publication date |
---|---|
CN115192717A (zh) | 2022-10-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR100997174B1 (ko) | 혈관 신생 억제제 | |
US11666574B2 (en) | Combination therapy involving diaryl macrocyclic compounds | |
CN104363913A (zh) | Cdk8/cdk19选择性抑制剂及其在癌症的抗转移和化学预防方法中的用途 | |
Fizazi et al. | Phase I, dose-finding, and pharmacokinetic study of raltitrexed combined with oxaliplatin in patients with advanced cancer | |
US20110123486A1 (en) | Methods of treating multiple myeloma and resistant cancers | |
M LoRusso et al. | Preclinical antitumor activity of XK469 (NSC 656889) | |
US20110070232A1 (en) | Combination Therapy with an Antitumor Alkaloid | |
CN109091480A (zh) | 癌组合物10-羟基喜树碱和克唑替尼治疗肺癌及用途 | |
EP1968981A2 (en) | A method of treating tumors with azaxanthones | |
CN113329772A (zh) | 化学疗法与重组齐整小核菌凝集素的联合疗法 | |
CN115192717B (zh) | 一种治疗癌症的药物组合物及其用途 | |
CN116390729A (zh) | 用于预防或治疗与ron突变相关的非小细胞肺癌的药物组合物及其使用方法 | |
CN115381956B (zh) | 一种治疗癌症的药物组合物及其用途 | |
JP2007186511A (ja) | 癌化学療法 | |
KR19990082064A (ko) | 피페라진 옥시란 유도체를 사용하여 신생 세포의 사멸을유도하는 방법 | |
JP2019206516A (ja) | 膵癌細胞の浸潤転移抑制剤 | |
WO2022028615A1 (zh) | 治疗肿瘤的方法 | |
JP7311177B2 (ja) | A-NOR-5αアンドロスタン薬物と抗がん薬物との併用 | |
CN101073561A (zh) | 结构类似Combretastatin A4的化合物在制备用于抑制微管蛋白聚合或抗肿瘤药物中的应用 | |
CN114642665A (zh) | 含有帕博西尼和10-羟基喜树碱的药物组合物及应用 | |
CN116685324A (zh) | 用于预防或治疗与ron突变相关的胰腺癌的药物组合物及其使用方法 | |
US20060052357A1 (en) | Organometallic anti-tumour agent | |
CN115137729B (zh) | 一种用于预防和/或治疗crc的小分子药物及其应用 | |
RU2726801C1 (ru) | Средство для терапии опухолей | |
KR0159934B1 (ko) | 항종양제 |
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 |