JP5718929B2 - 組合せ物 - Google Patents
組合せ物 Download PDFInfo
- Publication number
- JP5718929B2 JP5718929B2 JP2012534386A JP2012534386A JP5718929B2 JP 5718929 B2 JP5718929 B2 JP 5718929B2 JP 2012534386 A JP2012534386 A JP 2012534386A JP 2012534386 A JP2012534386 A JP 2012534386A JP 5718929 B2 JP5718929 B2 JP 5718929B2
- Authority
- JP
- Japan
- Prior art keywords
- cancer
- compound
- leukemia
- cell
- combination
- 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
- 150000001875 compounds Chemical class 0.000 claims description 251
- 206010028980 Neoplasm Diseases 0.000 claims description 115
- 201000011510 cancer Diseases 0.000 claims description 78
- 238000011282 treatment Methods 0.000 claims description 77
- 210000004027 cell Anatomy 0.000 claims description 75
- 239000003814 drug Substances 0.000 claims description 68
- 150000003839 salts Chemical class 0.000 claims description 58
- 239000008194 pharmaceutical composition Substances 0.000 claims description 37
- 239000012453 solvate Substances 0.000 claims description 37
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 25
- 208000032839 leukemia Diseases 0.000 claims description 21
- 206010006187 Breast cancer Diseases 0.000 claims description 18
- 201000010099 disease Diseases 0.000 claims description 18
- 208000026310 Breast neoplasm Diseases 0.000 claims description 17
- 201000001441 melanoma Diseases 0.000 claims description 16
- 239000003085 diluting agent Substances 0.000 claims description 14
- 206010033128 Ovarian cancer Diseases 0.000 claims description 13
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 13
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 11
- 206010009944 Colon cancer Diseases 0.000 claims description 11
- 206010025323 Lymphomas Diseases 0.000 claims description 11
- 208000034578 Multiple myelomas Diseases 0.000 claims description 11
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 11
- 208000005017 glioblastoma Diseases 0.000 claims description 10
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 10
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 9
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 9
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 9
- 206010060862 Prostate cancer Diseases 0.000 claims description 9
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 9
- 206010038389 Renal cancer Diseases 0.000 claims description 9
- 208000029742 colonic neoplasm Diseases 0.000 claims description 9
- 201000010982 kidney cancer Diseases 0.000 claims description 9
- 201000005202 lung cancer Diseases 0.000 claims description 9
- 208000020816 lung neoplasm Diseases 0.000 claims description 9
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 9
- 201000002528 pancreatic cancer Diseases 0.000 claims description 9
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 201000010536 head and neck cancer Diseases 0.000 claims description 8
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 7
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 7
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 7
- 206010057644 Testis cancer Diseases 0.000 claims description 7
- 201000003120 testicular cancer Diseases 0.000 claims description 7
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 6
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 6
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 6
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 6
- 206010014733 Endometrial cancer Diseases 0.000 claims description 6
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 6
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 6
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 6
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 6
- 201000002510 thyroid cancer Diseases 0.000 claims description 6
- 206010003571 Astrocytoma Diseases 0.000 claims description 5
- 206010005003 Bladder cancer Diseases 0.000 claims description 5
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 5
- 206010014967 Ependymoma Diseases 0.000 claims description 5
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 claims description 5
- 208000036566 Erythroleukaemia Diseases 0.000 claims description 5
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 5
- 208000008770 Multiple Hamartoma Syndrome Diseases 0.000 claims description 5
- 206010039491 Sarcoma Diseases 0.000 claims description 5
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 5
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 5
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 5
- 208000021841 acute erythroid leukemia Diseases 0.000 claims description 5
- 201000010881 cervical cancer Diseases 0.000 claims description 5
- 206010017758 gastric cancer Diseases 0.000 claims description 5
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 5
- 208000014018 liver neoplasm Diseases 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 201000011549 stomach cancer Diseases 0.000 claims description 5
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 5
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 4
- 208000012609 Cowden disease Diseases 0.000 claims description 4
- 208000032612 Glial tumor Diseases 0.000 claims description 4
- 206010018338 Glioma Diseases 0.000 claims description 4
- 208000008383 Wilms tumor Diseases 0.000 claims description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 4
- 201000003444 follicular lymphoma Diseases 0.000 claims description 4
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 201000008026 nephroblastoma Diseases 0.000 claims description 4
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 4
- 208000011580 syndromic disease Diseases 0.000 claims description 4
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 claims description 3
- 208000011691 Burkitt lymphomas Diseases 0.000 claims description 3
- 201000002847 Cowden syndrome Diseases 0.000 claims description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 3
- 208000006168 Ewing Sarcoma Diseases 0.000 claims description 3
- 208000007569 Giant Cell Tumors Diseases 0.000 claims description 3
- 201000010915 Glioblastoma multiforme Diseases 0.000 claims description 3
- 208000005726 Inflammatory Breast Neoplasms Diseases 0.000 claims description 3
- 206010021980 Inflammatory carcinoma of the breast Diseases 0.000 claims description 3
- 208000000172 Medulloblastoma Diseases 0.000 claims description 3
- 208000035490 Megakaryoblastic Acute Leukemia Diseases 0.000 claims description 3
- 206010027406 Mesothelioma Diseases 0.000 claims description 3
- 208000003445 Mouth Neoplasms Diseases 0.000 claims description 3
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 3
- 206010029260 Neuroblastoma Diseases 0.000 claims description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 3
- 208000007452 Plasmacytoma Diseases 0.000 claims description 3
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 claims description 3
- 206010061934 Salivary gland cancer Diseases 0.000 claims description 3
- 208000000389 T-cell leukemia Diseases 0.000 claims description 3
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 claims description 3
- 206010042971 T-cell lymphoma Diseases 0.000 claims description 3
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 3
- 206010047741 Vulval cancer Diseases 0.000 claims description 3
- 208000004354 Vulvar Neoplasms Diseases 0.000 claims description 3
- 208000037833 acute lymphoblastic T-cell leukemia Diseases 0.000 claims description 3
- 208000013593 acute megakaryoblastic leukemia Diseases 0.000 claims description 3
- 208000020700 acute megakaryocytic leukemia Diseases 0.000 claims description 3
- 230000001684 chronic effect Effects 0.000 claims description 3
- 201000004101 esophageal cancer Diseases 0.000 claims description 3
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims description 3
- 201000009277 hairy cell leukemia Diseases 0.000 claims description 3
- 201000004653 inflammatory breast carcinoma Diseases 0.000 claims description 3
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 claims description 3
- 210000000440 neutrophil Anatomy 0.000 claims description 3
- 201000008968 osteosarcoma Diseases 0.000 claims description 3
- 201000005102 vulva cancer Diseases 0.000 claims description 3
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 claims description 2
- 201000008806 mesenchymal cell neoplasm Diseases 0.000 claims description 2
- 230000002496 gastric effect Effects 0.000 claims 2
- 210000001685 thyroid gland Anatomy 0.000 claims 2
- 206010044412 transitional cell carcinoma Diseases 0.000 claims 2
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 claims 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 claims 1
- 238000011275 oncology therapy Methods 0.000 claims 1
- 229940126062 Compound A Drugs 0.000 description 115
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 115
- 229940079593 drug Drugs 0.000 description 59
- 239000003112 inhibitor Substances 0.000 description 59
- 235000002639 sodium chloride Nutrition 0.000 description 51
- 239000000203 mixture Substances 0.000 description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 40
- 239000002246 antineoplastic agent Substances 0.000 description 39
- -1 2-fluoro-4-iodo-phenylamino Chemical group 0.000 description 34
- 238000000034 method Methods 0.000 description 34
- 239000003795 chemical substances by application Substances 0.000 description 32
- 108091000080 Phosphotransferase Proteins 0.000 description 31
- 102000020233 phosphotransferase Human genes 0.000 description 31
- 230000000694 effects Effects 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- 230000005764 inhibitory process Effects 0.000 description 25
- 229940034982 antineoplastic agent Drugs 0.000 description 24
- 230000019491 signal transduction Effects 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- KKVYYGGCHJGEFJ-UHFFFAOYSA-N 1-n-(4-chlorophenyl)-6-methyl-5-n-[3-(7h-purin-6-yl)pyridin-2-yl]isoquinoline-1,5-diamine Chemical compound N=1C=CC2=C(NC=3C(=CC=CN=3)C=3C=4N=CNC=4N=CN=3)C(C)=CC=C2C=1NC1=CC=C(Cl)C=C1 KKVYYGGCHJGEFJ-UHFFFAOYSA-N 0.000 description 18
- 241000282414 Homo sapiens Species 0.000 description 18
- 101100381978 Mus musculus Braf gene Proteins 0.000 description 18
- 230000010261 cell growth Effects 0.000 description 18
- 239000007924 injection Substances 0.000 description 17
- 238000002347 injection Methods 0.000 description 17
- 239000010410 layer Substances 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- 102000001253 Protein Kinase Human genes 0.000 description 16
- 108060006633 protein kinase Proteins 0.000 description 16
- 230000022131 cell cycle Effects 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 15
- 230000035772 mutation Effects 0.000 description 15
- 102000016914 ras Proteins Human genes 0.000 description 15
- 230000004044 response Effects 0.000 description 14
- 239000003826 tablet Substances 0.000 description 14
- 108020004414 DNA Proteins 0.000 description 13
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 13
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 13
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- 230000037361 pathway Effects 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 230000011664 signaling Effects 0.000 description 12
- 108091007960 PI3Ks Proteins 0.000 description 11
- 102000038030 PI3Ks Human genes 0.000 description 11
- 229940127089 cytotoxic agent Drugs 0.000 description 11
- 239000000546 pharmaceutical excipient Substances 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- 108010014186 ras Proteins Proteins 0.000 description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
- 230000004913 activation Effects 0.000 description 10
- 238000001994 activation Methods 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 10
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 102000043136 MAP kinase family Human genes 0.000 description 9
- 108091054455 MAP kinase family Proteins 0.000 description 9
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 9
- 238000007792 addition Methods 0.000 description 9
- 208000035475 disorder Diseases 0.000 description 9
- 150000004141 diterpene derivatives Chemical class 0.000 description 9
- 230000012010 growth Effects 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 210000004881 tumor cell Anatomy 0.000 description 9
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 8
- 102000009465 Growth Factor Receptors Human genes 0.000 description 8
- 108010009202 Growth Factor Receptors Proteins 0.000 description 8
- 208000017604 Hodgkin disease Diseases 0.000 description 8
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 8
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 8
- 241000124008 Mammalia Species 0.000 description 8
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 8
- 229940122803 Vinca alkaloid Drugs 0.000 description 8
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 8
- 238000011068 loading method Methods 0.000 description 8
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 8
- 229910052697 platinum Inorganic materials 0.000 description 8
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 8
- 238000002560 therapeutic procedure Methods 0.000 description 8
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 7
- 229940124647 MEK inhibitor Drugs 0.000 description 7
- 229930012538 Paclitaxel Natural products 0.000 description 7
- 230000018199 S phase Effects 0.000 description 7
- 230000002159 abnormal effect Effects 0.000 description 7
- 230000009286 beneficial effect Effects 0.000 description 7
- 230000030833 cell death Effects 0.000 description 7
- 229940088597 hormone Drugs 0.000 description 7
- 238000012423 maintenance Methods 0.000 description 7
- 229960001592 paclitaxel Drugs 0.000 description 7
- 102200055464 rs113488022 Human genes 0.000 description 7
- 206010000830 Acute leukaemia Diseases 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 230000006820 DNA synthesis Effects 0.000 description 6
- 108010092160 Dactinomycin Proteins 0.000 description 6
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 6
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 108700020796 Oncogene Proteins 0.000 description 6
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 description 6
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 6
- 229940100198 alkylating agent Drugs 0.000 description 6
- 239000002168 alkylating agent Substances 0.000 description 6
- 239000004037 angiogenesis inhibitor Substances 0.000 description 6
- 238000013459 approach Methods 0.000 description 6
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 6
- 229940127093 camptothecin Drugs 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 6
- 210000001072 colon Anatomy 0.000 description 6
- 238000011161 development Methods 0.000 description 6
- 230000018109 developmental process Effects 0.000 description 6
- 239000003937 drug carrier Substances 0.000 description 6
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 6
- 239000005556 hormone Substances 0.000 description 6
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 6
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 150000007523 nucleic acids Chemical group 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-CFWMRBGOSA-N 0.000 description 6
- 229960003048 vinblastine Drugs 0.000 description 6
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 6
- 229960002066 vinorelbine Drugs 0.000 description 6
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 5
- 108010006654 Bleomycin Proteins 0.000 description 5
- 206010065553 Bone marrow failure Diseases 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 5
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 5
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 5
- 102000001301 EGF receptor Human genes 0.000 description 5
- 108060006698 EGF receptor Proteins 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 5
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 5
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 5
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 229960004562 carboplatin Drugs 0.000 description 5
- 230000024245 cell differentiation Effects 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- 208000025997 central nervous system neoplasm Diseases 0.000 description 5
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 5
- 229960004316 cisplatin Drugs 0.000 description 5
- 229960000684 cytarabine Drugs 0.000 description 5
- BFSMGDJOXZAERB-UHFFFAOYSA-N dabrafenib Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 BFSMGDJOXZAERB-UHFFFAOYSA-N 0.000 description 5
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 5
- 239000000890 drug combination Substances 0.000 description 5
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 5
- 239000012091 fetal bovine serum Substances 0.000 description 5
- 229960002949 fluorouracil Drugs 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 229960005277 gemcitabine Drugs 0.000 description 5
- 239000002944 hormone and hormone analog Substances 0.000 description 5
- 239000000314 lubricant Substances 0.000 description 5
- 230000001613 neoplastic effect Effects 0.000 description 5
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 5
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 102000039446 nucleic acids Human genes 0.000 description 5
- 108020004707 nucleic acids Proteins 0.000 description 5
- 230000026731 phosphorylation Effects 0.000 description 5
- 238000006366 phosphorylation reaction Methods 0.000 description 5
- 230000000861 pro-apoptotic effect Effects 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 238000002636 symptomatic treatment Methods 0.000 description 5
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 5
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 5
- 229960004528 vincristine Drugs 0.000 description 5
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 5
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 5
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 108091007914 CDKs Proteins 0.000 description 4
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- 102000053602 DNA Human genes 0.000 description 4
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 4
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 4
- 101000876610 Dictyostelium discoideum Extracellular signal-regulated kinase 2 Proteins 0.000 description 4
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 4
- 101001052493 Homo sapiens Mitogen-activated protein kinase 1 Proteins 0.000 description 4
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 4
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 102000014400 SH2 domains Human genes 0.000 description 4
- 108050003452 SH2 domains Proteins 0.000 description 4
- 102000000395 SH3 domains Human genes 0.000 description 4
- 108050008861 SH3 domains Proteins 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 4
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 4
- 150000001413 amino acids Chemical group 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 230000000340 anti-metabolite Effects 0.000 description 4
- 230000001946 anti-microtubular Effects 0.000 description 4
- 229940100197 antimetabolite Drugs 0.000 description 4
- 239000002256 antimetabolite Substances 0.000 description 4
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 229960001561 bleomycin Drugs 0.000 description 4
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 4
- 230000032823 cell division Effects 0.000 description 4
- 210000003169 central nervous system Anatomy 0.000 description 4
- 201000007455 central nervous system cancer Diseases 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 229960000640 dactinomycin Drugs 0.000 description 4
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 229960003668 docetaxel Drugs 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 229960005420 etoposide Drugs 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 229960004768 irinotecan Drugs 0.000 description 4
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 4
- 230000000670 limiting effect Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 230000003211 malignant effect Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229960001924 melphalan Drugs 0.000 description 4
- 229960001428 mercaptopurine Drugs 0.000 description 4
- 229960000485 methotrexate Drugs 0.000 description 4
- 230000007170 pathology Effects 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 230000002062 proliferating effect Effects 0.000 description 4
- 108010077182 raf Kinases Proteins 0.000 description 4
- 102000009929 raf Kinases Human genes 0.000 description 4
- 108700042226 ras Genes Proteins 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 229960003087 tioguanine Drugs 0.000 description 4
- 229960000303 topotecan Drugs 0.000 description 4
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 4
- 239000001993 wax Substances 0.000 description 4
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 3
- 208000003174 Brain Neoplasms Diseases 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 3
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 3
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 3
- 102000003915 DNA Topoisomerases Human genes 0.000 description 3
- 108090000323 DNA Topoisomerases Proteins 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 3
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- 108091008606 PDGF receptors Proteins 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 3
- 108091008611 Protein Kinase B Proteins 0.000 description 3
- 108091005682 Receptor kinases Proteins 0.000 description 3
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 208000000453 Skin Neoplasms Diseases 0.000 description 3
- 206010041067 Small cell lung cancer Diseases 0.000 description 3
- 102000004142 Trypsin Human genes 0.000 description 3
- 108090000631 Trypsin Proteins 0.000 description 3
- 102000004243 Tubulin Human genes 0.000 description 3
- 108090000704 Tubulin Proteins 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 3
- 239000000074 antisense oligonucleotide Substances 0.000 description 3
- 238000012230 antisense oligonucleotides Methods 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229960002092 busulfan Drugs 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 229960005243 carmustine Drugs 0.000 description 3
- 238000012054 celltiter-glo Methods 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 229960004630 chlorambucil Drugs 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 230000002301 combined effect Effects 0.000 description 3
- 230000006552 constitutive activation Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 229960004397 cyclophosphamide Drugs 0.000 description 3
- 229960003901 dacarbazine Drugs 0.000 description 3
- 229960000975 daunorubicin Drugs 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 229960004679 doxorubicin Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 229940014259 gelatin Drugs 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 239000002955 immunomodulating agent Substances 0.000 description 3
- 238000009169 immunotherapy Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 108010082117 matrigel Proteins 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000001394 metastastic effect Effects 0.000 description 3
- 206010061289 metastatic neoplasm Diseases 0.000 description 3
- COSCWKICERLCEK-UHFFFAOYSA-N methyl 3-[(2,6-difluorophenyl)sulfonylamino]-2-fluorobenzoate Chemical compound COC(=O)C1=CC=CC(NS(=O)(=O)C=2C(=CC=CC=2F)F)=C1F COSCWKICERLCEK-UHFFFAOYSA-N 0.000 description 3
- 230000011278 mitosis Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- JENXIOQPSJSXEN-UHFFFAOYSA-N n-[3-[2-(2-chloropyrimidin-4-yl)acetyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide Chemical compound FC1=CC=CC(F)=C1S(=O)(=O)NC1=CC=CC(C(=O)CC=2N=C(Cl)N=CC=2)=C1F JENXIOQPSJSXEN-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000006072 paste Substances 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 102000040430 polynucleotide Human genes 0.000 description 3
- 108091033319 polynucleotide Proteins 0.000 description 3
- 239000002157 polynucleotide Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 238000011519 second-line treatment Methods 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 201000000849 skin cancer Diseases 0.000 description 3
- 208000000587 small cell lung carcinoma Diseases 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 229960001278 teniposide Drugs 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 238000011200 topical administration Methods 0.000 description 3
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 description 3
- OQUFJVRYDFIQBW-UHFFFAOYSA-N trametinib dimethyl sulfoxide Chemical compound CS(C)=O.CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 OQUFJVRYDFIQBW-UHFFFAOYSA-N 0.000 description 3
- 239000012588 trypsin Substances 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- 238000012447 xenograft mouse model Methods 0.000 description 3
- FOVRGQUEGRCWPD-UHFFFAOYSA-N (5aR)-9t-beta-D-Glucopyranosyloxy-5t-(4-hydroxy-3,5-dimethoxy-phenyl)-(5ar,8at)-5,8,8a,9-tetrahydro-5aH-furo[3',4';6,7]naphtho[2,3-d][1,3]dioxol-6-on Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(OC3C(C(O)C(O)C(CO)O3)O)C3C2C(OC3)=O)=C1 FOVRGQUEGRCWPD-UHFFFAOYSA-N 0.000 description 2
- YJGVMLPVUAXIQN-LGWHJFRWSA-N (5s,5ar,8ar,9r)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5h-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-LGWHJFRWSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- DWBWMAAYLWUXQK-UHFFFAOYSA-N 2,3-difluorobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC(F)=C1F DWBWMAAYLWUXQK-UHFFFAOYSA-N 0.000 description 2
- YVCVYCSAAZQOJI-JHQYFNNDSA-N 4'-demethylepipodophyllotoxin Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YVCVYCSAAZQOJI-JHQYFNNDSA-N 0.000 description 2
- YWLXLRUDGLRYDR-ZHPRIASZSA-N 5beta,20-epoxy-1,7beta,10beta,13alpha-tetrahydroxy-9-oxotax-11-ene-2alpha,4alpha-diyl 4-acetate 2-benzoate Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-ZHPRIASZSA-N 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 229940125431 BRAF inhibitor Drugs 0.000 description 2
- 208000029862 Barrett adenocarcinoma Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 102000016736 Cyclin Human genes 0.000 description 2
- 108050006400 Cyclin Proteins 0.000 description 2
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 2
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 2
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 2
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 2
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 2
- 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 102000007317 Farnesyltranstransferase Human genes 0.000 description 2
- 108010007508 Farnesyltranstransferase Proteins 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 2
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 2
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 206010069755 K-ras gene mutation Diseases 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- 108010058398 Macrophage Colony-Stimulating Factor Receptor Proteins 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 102000029749 Microtubule Human genes 0.000 description 2
- 108091022875 Microtubule Proteins 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- 101150111783 NTRK1 gene Proteins 0.000 description 2
- 101150117329 NTRK3 gene Proteins 0.000 description 2
- 101150056950 Ntrk2 gene Proteins 0.000 description 2
- 102000043276 Oncogene Human genes 0.000 description 2
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 2
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 108090000315 Protein Kinase C Proteins 0.000 description 2
- 102000003923 Protein Kinase C Human genes 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000012979 RPMI medium Substances 0.000 description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 2
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 101710183280 Topoisomerase Proteins 0.000 description 2
- 102100029823 Tyrosine-protein kinase BTK Human genes 0.000 description 2
- 108091008605 VEGF receptors Proteins 0.000 description 2
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 229930183665 actinomycin Natural products 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 2
- 150000008052 alkyl sulfonates Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 229940045799 anthracyclines and related substance Drugs 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940044684 anti-microtubule agent Drugs 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 238000011319 anticancer therapy Methods 0.000 description 2
- 239000003080 antimitotic agent Substances 0.000 description 2
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 235000012216 bentonite Nutrition 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- 201000009036 biliary tract cancer Diseases 0.000 description 2
- 208000020790 biliary tract neoplasm Diseases 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229940105329 carboxymethylcellulose Drugs 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 230000010307 cell transformation Effects 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- OHNBIIZWIUBGTK-NYPSMHOZSA-N cid_23581792 Chemical compound O.Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 OHNBIIZWIUBGTK-NYPSMHOZSA-N 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 229940000425 combination drug Drugs 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 229960001334 corticosteroids Drugs 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- GYOZYWVXFNDGLU-XLPZGREQSA-N dTMP Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)C1 GYOZYWVXFNDGLU-XLPZGREQSA-N 0.000 description 2
- 230000003831 deregulation Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229940126864 fibroblast growth factor Drugs 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 2
- 229960000961 floxuridine Drugs 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 229940028334 follicle stimulating hormone Drugs 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 2
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229940102223 injectable solution Drugs 0.000 description 2
- 229960000367 inositol Drugs 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 108020001756 ligand binding domains Proteins 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 208000037819 metastatic cancer Diseases 0.000 description 2
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 2
- 210000004688 microtubule Anatomy 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- IOJHPWJJWDACRN-UHFFFAOYSA-N n-[3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(Cl)=N1 IOJHPWJJWDACRN-UHFFFAOYSA-N 0.000 description 2
- 229940097496 nasal spray Drugs 0.000 description 2
- 239000007922 nasal spray Substances 0.000 description 2
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000003883 ointment base Substances 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 239000011236 particulate material Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 238000007747 plating Methods 0.000 description 2
- 208000030761 polycystic kidney disease Diseases 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 102000054765 polymorphisms of proteins Human genes 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 150000003212 purines Chemical class 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000021014 regulation of cell growth Effects 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 2
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 2
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007921 spray Substances 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
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 102000035160 transmembrane proteins Human genes 0.000 description 2
- 108091005703 transmembrane proteins Proteins 0.000 description 2
- 150000004654 triazenes Chemical class 0.000 description 2
- 239000002691 unilamellar liposome Substances 0.000 description 2
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- RGHNJXZEOKUKBD-NRXMZTRTSA-N (2r,3r,4r,5s)-2,3,4,5,6-pentahydroxyhexanoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-NRXMZTRTSA-N 0.000 description 1
- JNSWIYCWZPFQQF-JGVFFNPUSA-N (2r,3s)-3-(carboxyamino)-2-hydroxy-3-phenylpropanoic acid Chemical compound OC(=O)[C@H](O)[C@@H](NC(O)=O)C1=CC=CC=C1 JNSWIYCWZPFQQF-JGVFFNPUSA-N 0.000 description 1
- CRYXXTXWUCPIMU-WNQIDUERSA-N (2s)-2-aminobutanediamide;phenol Chemical compound OC1=CC=CC=C1.NC(=O)[C@@H](N)CC(N)=O CRYXXTXWUCPIMU-WNQIDUERSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 1
- FJZJUSOFGBXHCV-UHFFFAOYSA-N 2,2-dimethylpropanethioamide Chemical compound CC(C)(C)C(N)=S FJZJUSOFGBXHCV-UHFFFAOYSA-N 0.000 description 1
- RVVVGGCOFWWDEL-UHFFFAOYSA-N 2,6-difluorobenzenesulfonamide Chemical compound NS(=O)(=O)C1=C(F)C=CC=C1F RVVVGGCOFWWDEL-UHFFFAOYSA-N 0.000 description 1
- QXWAUQMMMIMLTO-UHFFFAOYSA-N 2,6-difluorobenzenesulfonyl chloride Chemical compound FC1=CC=CC(F)=C1S(Cl)(=O)=O QXWAUQMMMIMLTO-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- BHAKRVSCGILCEW-UHFFFAOYSA-N 2-chloro-4-methylpyrimidine Chemical compound CC1=CC=NC(Cl)=N1 BHAKRVSCGILCEW-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- OPJKGTJXHVPYIM-UHFFFAOYSA-N 2-methylprop-2-enamide;phenol Chemical compound CC(=C)C(N)=O.OC1=CC=CC=C1 OPJKGTJXHVPYIM-UHFFFAOYSA-N 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- WUIABRMSWOKTOF-OYALTWQYSA-N 3-[[2-[2-[2-[[(2s,3r)-2-[[(2s,3s,4r)-4-[[(2s,3r)-2-[[6-amino-2-[(1s)-3-amino-1-[[(2s)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2r,3s,4s,5s,6s)-3-[(2r,3s,4s,5r,6r)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)ox Chemical compound OS([O-])(=O)=O.N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C WUIABRMSWOKTOF-OYALTWQYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-M 3-carboxynaphthalen-2-olate Chemical compound C1=CC=C2C=C(C([O-])=O)C(O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-M 0.000 description 1
- PMHOWXRNJXWYIP-UHFFFAOYSA-N 4,5-dihydrooxazaphosphole Chemical class C1CP=NO1 PMHOWXRNJXWYIP-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- HFEKDTCAMMOLQP-RRKCRQDMSA-N 5-fluorodeoxyuridine monophosphate Chemical compound O1[C@H](COP(O)(O)=O)[C@@H](O)C[C@@H]1N1C(=O)NC(=O)C(F)=C1 HFEKDTCAMMOLQP-RRKCRQDMSA-N 0.000 description 1
- RGBUBXPAZXBNMI-UHFFFAOYSA-N 6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione;hydrochloride Chemical compound Cl.C1C(O)CCC2=C1C(O)=C1C(=O)C(C=CC=C3OC)=C3C(=O)C1=C2O RGBUBXPAZXBNMI-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102100022014 Angiopoietin-1 receptor Human genes 0.000 description 1
- 102400000068 Angiostatin Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 201000007815 Bannayan-Riley-Ruvalcaba syndrome Diseases 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 0 CC(Nc1cc(N(C(C(C(N2C3CC3)=*)=C(Nc(ccc(I)c3)c3F)N3C)=C(C)C3=O)C2=O)ccc1)=O Chemical compound CC(Nc1cc(N(C(C(C(N2C3CC3)=*)=C(Nc(ccc(I)c3)c3F)N3C)=C(C)C3=O)C2=O)ccc1)=O 0.000 description 1
- RRXPXILEZMIDKP-UHFFFAOYSA-N CS(=O)(=O)O.NC1=NC=CC(=N1)C1=C(N=C(S1)C(C)(C)C)C=1C(=C(C=CC1)NS(=O)(=O)C1=C(C=CC=C1F)F)F.S(C)(=O)(=O)O Chemical compound CS(=O)(=O)O.NC1=NC=CC(=N1)C1=C(N=C(S1)C(C)(C)C)C=1C(=C(C=CC1)NS(=O)(=O)C1=C(C=CC=C1F)F)F.S(C)(=O)(=O)O RRXPXILEZMIDKP-UHFFFAOYSA-N 0.000 description 1
- 108010026870 Calcium-Calmodulin-Dependent Protein Kinases Proteins 0.000 description 1
- 102000019025 Calcium-Calmodulin-Dependent Protein Kinases Human genes 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 201000002927 Cardiofaciocutaneous syndrome Diseases 0.000 description 1
- 108010031425 Casein Kinases Proteins 0.000 description 1
- 102000005403 Casein Kinases Human genes 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 102000005483 Cell Cycle Proteins Human genes 0.000 description 1
- 108010031896 Cell Cycle Proteins Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 108010066551 Cholestenone 5 alpha-Reductase Proteins 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 1
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 1
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 1
- 102000004654 Cyclic GMP-Dependent Protein Kinases Human genes 0.000 description 1
- 108010003591 Cyclic GMP-Dependent Protein Kinases Proteins 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- 238000000018 DNA microarray Methods 0.000 description 1
- 231100001074 DNA strand break Toxicity 0.000 description 1
- GUGHGUXZJWAIAS-QQYBVWGSSA-N Daunorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 GUGHGUXZJWAIAS-QQYBVWGSSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- 101100015729 Drosophila melanogaster drk gene Proteins 0.000 description 1
- 102000054300 EC 2.7.11.- Human genes 0.000 description 1
- 108700035490 EC 2.7.11.- Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102100030013 Endoribonuclease Human genes 0.000 description 1
- 101710199605 Endoribonuclease Proteins 0.000 description 1
- 102400001047 Endostatin Human genes 0.000 description 1
- 108010079505 Endostatins Proteins 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 1
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- QGWNDRXFNXRZMB-UUOKFMHZSA-N GDP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O QGWNDRXFNXRZMB-UUOKFMHZSA-N 0.000 description 1
- 102000013446 GTP Phosphohydrolases Human genes 0.000 description 1
- 102100030708 GTPase KRas Human genes 0.000 description 1
- 108091006109 GTPases Proteins 0.000 description 1
- 206010064147 Gastrointestinal inflammation Diseases 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-N 0.000 description 1
- 101000753291 Homo sapiens Angiopoietin-1 receptor Proteins 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 1
- 101000864342 Homo sapiens Tyrosine-protein kinase BTK Proteins 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- 206010062904 Hormone-refractory prostate cancer Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 101150057269 IKBKB gene Proteins 0.000 description 1
- JJKOTMDDZAJTGQ-DQSJHHFOSA-N Idoxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN2CCCC2)=CC=1)/C1=CC=C(I)C=C1 JJKOTMDDZAJTGQ-DQSJHHFOSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 108010047852 Integrin alphaVbeta3 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 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
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 1
- 208000035561 Leukaemic infiltration brain Diseases 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- LPGWZGMPDKDHEP-HLTPFJCJSA-N Leurosine Chemical compound C([C@]1([C@@H]2O1)CC)N(CCC=1C3=CC=CC=C3NC=11)C[C@H]2C[C@]1(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC LPGWZGMPDKDHEP-HLTPFJCJSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000030070 Malignant epithelial tumor of ovary Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 1
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 1
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 238000000636 Northern blotting Methods 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- 208000007571 Ovarian Epithelial Carcinoma Diseases 0.000 description 1
- 206010061328 Ovarian epithelial cancer Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229920002230 Pectic acid Chemical class 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
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 1
- 201000005746 Pituitary adenoma Diseases 0.000 description 1
- 206010061538 Pituitary tumour benign Diseases 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 244000236480 Podophyllum peltatum Species 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 108010029869 Proto-Oncogene Proteins c-raf Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- 102000003901 Ras GTPase-activating proteins Human genes 0.000 description 1
- 108090000231 Ras GTPase-activating proteins Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 108060006706 SRC Proteins 0.000 description 1
- 102000001332 SRC Human genes 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 241001147844 Streptomyces verticillus Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 108091005735 TGF-beta receptors Proteins 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 241001116498 Taxus baccata Species 0.000 description 1
- 241000202349 Taxus brevifolia Species 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 102000016715 Transforming Growth Factor beta Receptors Human genes 0.000 description 1
- 102000014384 Type C Phospholipases Human genes 0.000 description 1
- 108010079194 Type C Phospholipases Proteins 0.000 description 1
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 1
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 1
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 241000863480 Vinca Species 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229940098174 alkeran Drugs 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 229920000469 amphiphilic block copolymer Polymers 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000003432 anti-folate effect Effects 0.000 description 1
- 230000003302 anti-idiotype Effects 0.000 description 1
- 230000001740 anti-invasion Effects 0.000 description 1
- 230000002137 anti-vascular effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 229940125644 antibody drug Drugs 0.000 description 1
- 229940127074 antifolate Drugs 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 239000008122 artificial sweetener Substances 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 238000003705 background correction Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 229940108502 bicnu Drugs 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 108010025267 calcium-dependent protein kinase Proteins 0.000 description 1
- 229940088954 camptosar Drugs 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000000006 cell growth inhibition assay Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000009087 cell motility Effects 0.000 description 1
- 230000009134 cell regulation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 101150116749 chuk gene Proteins 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 229940090805 clavulanate Drugs 0.000 description 1
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 229940088547 cosmegen Drugs 0.000 description 1
- 229920006037 cross link polymer Polymers 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940095074 cyclic amp Drugs 0.000 description 1
- CCQPAEQGAVNNIA-UHFFFAOYSA-L cyclobutane-1,1-dicarboxylate(2-) Chemical compound [O-]C(=O)C1(C([O-])=O)CCC1 CCQPAEQGAVNNIA-UHFFFAOYSA-L 0.000 description 1
- 229960000978 cyproterone acetate Drugs 0.000 description 1
- UWFYSQMTEOIJJG-FDTZYFLXSA-N cyproterone acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 UWFYSQMTEOIJJG-FDTZYFLXSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical class O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229940107841 daunoxome Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- ACYGYJFTZSAZKR-UHFFFAOYSA-J dicalcium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Ca+2].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O ACYGYJFTZSAZKR-UHFFFAOYSA-J 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical class [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 101150042537 dld1 gene Proteins 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 230000005782 double-strand break Effects 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 210000001951 dura mater Anatomy 0.000 description 1
- 229940009662 edetate Drugs 0.000 description 1
- 230000002888 effect on disease Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 229950005627 embonate Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 102000012803 ephrin Human genes 0.000 description 1
- 108060002566 ephrin Proteins 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 239000005454 flavour additive Substances 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229960005304 fludarabine phosphate Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 150000005699 fluoropyrimidines Chemical class 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 210000001650 focal adhesion Anatomy 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 208000018925 gastrointestinal mucositis Diseases 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- OKKDEIYWILRZIA-OSZBKLCCSA-N gemcitabine hydrochloride Chemical compound [H+].[Cl-].O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 OKKDEIYWILRZIA-OSZBKLCCSA-N 0.000 description 1
- 229940020967 gemzar Drugs 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 238000012239 gene modification Methods 0.000 description 1
- 230000005017 genetic modification Effects 0.000 description 1
- 235000013617 genetically modified food Nutrition 0.000 description 1
- 125000002686 geranylgeranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- 229960003690 goserelin acetate Drugs 0.000 description 1
- 101150098203 grb2 gene Proteins 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- QGWNDRXFNXRZMB-UHFFFAOYSA-N guanidine diphosphate Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O QGWNDRXFNXRZMB-UHFFFAOYSA-N 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 229940088013 hycamtin Drugs 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 239000008309 hydrophilic cream Substances 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000003365 immunocytochemistry Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 229940028885 interleukin-4 Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 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 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 229940063725 leukeran Drugs 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 230000000938 luteal effect Effects 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 208000025036 lymphosarcoma Diseases 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 208000026037 malignant tumor of neck Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- WFFQYWAAEWLHJC-UHFFFAOYSA-N mercaptopurine hydrate Chemical compound O.S=C1NC=NC2=C1NC=N2 WFFQYWAAEWLHJC-UHFFFAOYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 208000021039 metastatic melanoma Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- DASQOOZCTWOQPA-GXKRWWSZSA-L methotrexate disodium Chemical compound [Na+].[Na+].C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 DASQOOZCTWOQPA-GXKRWWSZSA-L 0.000 description 1
- 229960003058 methotrexate sodium Drugs 0.000 description 1
- UOYDNSRSUSNCKS-UHFFFAOYSA-N methyl 3-amino-2-fluorobenzoate Chemical compound COC(=O)C1=CC=CC(N)=C1F UOYDNSRSUSNCKS-UHFFFAOYSA-N 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- LRMHVVPPGGOAJQ-UHFFFAOYSA-N methyl nitrate Chemical compound CO[N+]([O-])=O LRMHVVPPGGOAJQ-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 230000035773 mitosis phase Effects 0.000 description 1
- 238000002625 monoclonal antibody therapy Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 230000000869 mutational effect Effects 0.000 description 1
- 229940090009 myleran Drugs 0.000 description 1
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 1
- BLCLNMBMMGCOAS-UHFFFAOYSA-N n-[1-[[1-[[1-[[1-[[1-[[1-[[1-[2-[(carbamoylamino)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amin Chemical compound C1CCC(C(=O)NNC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)C(COC(C)(C)C)NC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 BLCLNMBMMGCOAS-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 125000005487 naphthalate group Chemical group 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 230000017095 negative regulation of cell growth Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 229960003552 other antineoplastic agent in atc Drugs 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 208000021310 pituitary gland adenoma Diseases 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940063179 platinol Drugs 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000010318 polygalacturonic acid Chemical class 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- QPMDWIOUHQWKHV-ODZAUARKSA-M potassium;(z)-4-hydroxy-4-oxobut-2-enoate Chemical compound [K+].OC(=O)\C=C/C([O-])=O QPMDWIOUHQWKHV-ODZAUARKSA-M 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000009117 preventive therapy Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 201000002025 prostate sarcoma Diseases 0.000 description 1
- 239000011253 protective coating Substances 0.000 description 1
- 239000002213 purine nucleotide Substances 0.000 description 1
- 229940117820 purinethol Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 239000012066 reaction slurry Substances 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 102200055451 rs121913361 Human genes 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000009094 second-line therapy Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 230000005783 single-strand break Effects 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 102000009076 src-Family Kinases Human genes 0.000 description 1
- 108010087686 src-Family Kinases Proteins 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940095374 tabloid Drugs 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- RCINICONZNJXQF-XAZOAEDWSA-N taxol® Chemical compound O([C@@H]1[C@@]2(CC(C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3(C21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-XAZOAEDWSA-N 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 230000002381 testicular Effects 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 239000003104 tissue culture media Substances 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 229960002166 vinorelbine tartrate Drugs 0.000 description 1
- GBABOYUKABKIAF-IWWDSPBFSA-N vinorelbinetartrate Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC(C23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IWWDSPBFSA-N 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (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)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
バレット腺癌(Garnettら、Cancer Cell (2004) 6 313−319およびSommererら、Oncogene (2004) 23(2) 554−558)、胆道癌(Zebischら、Cell. Mol. Life Sci. (2006) 63 1314−1330)、乳癌(Davies (2002) 前出)、子宮頸癌(Moreno−Buenoら、Clin. Cancer Res. (2006) 12(12) 3865−3866)、胆管細胞癌(Tannapfelら、Gut (2003) 52(5) 706−712)、神経膠芽腫、星状細胞腫および上衣腫などの原発性中枢神経系腫瘍を含めた中枢神経系腫瘍(Knobbeら、Acta Neuropathol. (Berl.) (2004) 108(6) 467−470、Davies (2002) 前出、およびGarnettら、Cancer Cell (2004) 前出)ならびに続発性中枢神経系腫瘍(すなわち、中枢神経系の外に由来する腫瘍の、中枢神経系への転移)、大腸結腸癌を含めた結直腸癌(Yuenら、Cancer Res. (2002) 62(22) 6451−6455、Davies (2002) 前出およびZebischら、Cell. Mol. Life Sci. (2006)、胃癌(Leeら、Oncogene (2003) 22(44) 6942−6945)、頭頸部扁平上皮癌を含めた頭頸部の癌(Cohenら、J. Nat. Cancer Inst. (2003) 95(8) 625−627およびWeberら、Oncogene (2003) 22(30) 4757−4759)、白血病(Garnettら、Cancer Cell (2004) 前出、特に急性リンパ芽球性白血病(Garnettら、Cancer Cell (2004) 前出およびGustafssonら、Leukemia (2005) 19(2) 310−312)、急性骨髄性白血病(AML)(Leeら、Leukemia (2004) 18(1) 170−172、およびChristiansenら、Leukemia (2005) 19(12) 2232−2240)、骨髄異形成症候群(Christiansenら、Leukemia (2005) 前出)および慢性骨髄性白血病(Mizuchiら、Biochem. Biophys. Res. Commun. (2005) 326(3) 645−651);ホジキンリンパ腫(Figlら、Arch. Dermatol. (2007) 143(4) 495−499)、非ホジキンリンパ腫(Leeら、Br. J. Cancer (2003) 89(10) 1958−1960)、巨核芽球性白血病(Eycheneら、Oncogene (1995) 10(6) 1159−1165)および多発性骨髄腫(Ngら、Br. J. Haematol. (2003) 123(4) 637−645)を含めた血液癌、肝細胞癌(Garnettら、Cancer Cell (2004)、
小細胞性肺癌(Pardoら、EMBO J. (2006) 25(13) 3078−3088)および非小細胞性肺癌(Davies (2002) 前出)を含めた肺癌(Broseら、Cancer Res. (2002) 62(23) 6997−7000、Cohenら、J. Nat. Cancer Inst. (2003) 前出およびDavies (2002) 前出)、卵巣癌(RussellおよびMcCluggage J. Pathol. (2004) 203(2) 617−619およびDavies (2002) 前出)、子宮内膜癌(Garnettら、Cancer Cell (2004) 前出、およびMoreno−Buenoら、Clin. Cancer Res. (2006) 前出)、膵臓癌(Ishimuraら、Cancer Lett. (2003) 199(2) 169−173)、下垂体腺腫(De Martinoら、J. Endocrinol. Invest. (2007) 30(1) RC1−3)、前立腺癌(Choら、Int. J. Cancer (2006) 119(8) 1858−1862)、腎癌(Nagyら、Int. J. Cancer (2003) 106(6) 980−981)、肉腫(Davies (2002) 前出)、および皮膚癌(Rodriguez−Vicianaら、Science (2006) 311(5765) 1287−1290およびDavies(2002) 前出)。c−Rafの過剰発現はAML(Zebischら、Cancer Res. (2006) 66(7) 3401−3408、およびZebisch(Cell. Mol. Life Sci. (2006))および赤白血病(Zebischら、Cell. Mol. Life Sci. (2006)に結びつけられてきた。
を含む組合せ物が提供される。
を含む組合せ物が提供される。
を含む組合せ物が提供される。
を、薬学上許容可能な希釈剤または担体と一緒に含む医薬組成物が提供される。
を含む組合せ物の使用が提供される。
19.6mgのN−{3−[5−(2−アミノ−4−ピリミジニル)−2−(1,1−ジメチルエチル)−1,3−チアゾール−4−イル]−2−フルオロフェニル}−2,6−ジフルオロベンゼンスルホンアミド(実施例58aに従って調製され得る)を、室温で、2mLのバイアルの中で、500Lの酢酸エチルと合わせた。このスラリーを、48時間、0−40℃の間で温度サイクルにかけた。得られたスラリーを室温まで冷却し、固体を減圧ろ過によって集めた。この固体をラマン、PXRD、DSC/TGA分析によって分析すると、上記の実施例58aから得られた結晶形態とは異なる結晶形態であることが示された。
1galの圧力反応器の中で、上記の工程Cに従って調製したN−{3−[5−(2−クロロ−4−ピリミジニル)−2−(1,1−ジメチルエチル)−1,3−チアゾール−4−イル]−2−フルオロフェニル}−2,6−ジフルオロベンゼンスルホンアミド(120g)、および水酸化アンモニウム(28−30%、2.4L、20倍量)の混合物を、密閉した圧力反応器の中で98−103℃に加熱し、この温度で2時間撹拌した。この反応液を室温(20℃)までゆっくり冷却し、一晩撹拌した。固体をろ過し、最小量の母液で洗浄し、真空下で乾燥した。この固体をEtOAc(15倍量)/水(2倍量)の混合物に添加し、完全に溶解するまで60−70℃で加熱し、水層を除去し、捨てた。このEtOAC層に水(1倍量)を入れ、HCl水溶液を用いてpH 約5.4−5.5まで中和し、水(1倍量)を添加した。60−70℃で水層を除去し、捨てた。60−70℃で有機層を水(1倍量)で洗浄し、水層を除去し、捨てた。有機層を60℃でろ過し、3倍量まで濃縮した。EtOAc(6倍量)をこの混合物に加え、加熱し、72℃で10分間撹拌し、次いで20℃に冷却し、一晩撹拌した。真空蒸留によってEtOAcを除去し、反応混合物を約3倍量まで濃縮した。この反応混合物を、約65−70℃で約30分間維持した。上記の実施例58bでヘプタンスラリーの中で調製した(そして、実施例58bの手順によって調製できる)結晶と同じ結晶形態を有する生成物の結晶を加えた。65−70℃でヘプタン(9倍量)をゆっくり添加した。このスラリーを65−70℃で2−3時間撹拌し、次いで0−5℃にゆっくり冷却した。生成物をろ過し、EtOAc/ヘプタン(3/1 v/v、4倍量)で洗浄し、真空下、45℃で乾燥し、N−{3−[5−(2−アミノ−4−ピリミジニル)−2−(1,1−ジメチルエチル)−1,3−チアゾール−4−イル]−2−フルオロフェニル}−2,6−ジフルオロベンゼンスルホンアミド(102.3g、88%)を得た。
N−{3−[5−(2−アミノ−4−ピリミジニル)−2−(1,1−ジメチルエチル)−1,3−チアゾール−4−イル]−2−フルオロフェニル}−2,6−ジフルオロベンゼンスルホンアミド(実施例58aに従って調製し得る)(2.37g、4.56mmol)を、予めろ過したアセトニトリル(5.25倍量、12.4mL)と合わせた。H2O(0.75当量、1.78mL)中のメシン酸(1.1当量、5.02mmol、0.48g)の予めろ過した溶液を20℃で添加した。低い撹拌速度を維持しながら、得られた混合物の温度を50−60℃に上げた。混合物の温度が50−60℃に到達すると、N−{3−[5−(2−アミノ−4−ピリミジニル)−2−(1,1−ジメチルエチル)−1,3−チアゾール−4−イル]−2−フルオロフェニル}−2,6−ジフルオロベンゼンスルホンアミド メタンスルホネートの種スラリー(0.2倍量の予めろ過したアセトニトリルの中でスラリーにした1.0% w/w)を添加し、固体が沈降しないようにするのに十分速い速度で撹拌しながら、この混合物を50−60℃で2時間熟成させた。次いでこの混合物を0.25℃/分で0−5℃まで冷却し、0−5℃で6時間保持した。この混合物をろ過し、湿ったケーキを、予めろ過したアセトニトリルを用いて2回洗浄した。最初の洗液は14.2ml(6倍量)の予めろ過したアセトニトリルからなっており、第2の洗液は9.5ml(4倍量)の予めろ過したアセトニトリルからなっていた。この湿ったケーキを真空下、50℃で乾燥し、2.39g(85.1%収率)の生成物を得た。
薬学上許容可能な賦形剤、希釈剤または担体を伴う化合物Aと、
薬学上許容可能な賦形剤、希釈剤または担体を伴う化合物Bと、
という構成要素を含むキット・オブ・パーツが提供される。
薬学上許容可能な賦形剤、希釈剤または担体を伴う化合物Aと、
薬学上許容可能な賦形剤、希釈剤または担体を伴う化合物Bと、
を含み、これらの要素は、逐次投与、別々の投与および/または同時投与に適した形態で提供される。
薬学上許容可能な賦形剤、希釈剤または担体を伴う化合物Aを含む第1の容器と、
薬学上許容可能な賦形剤、希釈剤または担体を伴う化合物Bを含む第2の容器と、
この第1および第2の容器を収容するための容器手段と、
を含む。
好適には、両方の化合物は、ある特定期間内で少なくとも1日投与されることになり − この場合、継続期間は少なくとも1日ということになり;好適には、治療への過程の間に、両方の化合物は、ある特定期間内で少なくとも連続3日投与されることになり − この場合、継続期間は少なくとも3日ということになり;好適には、治療への過程の間に、両方の化合物は、ある特定期間内で少なくとも連続5日投与されることになり − この場合、継続期間は少なくとも5日ということになり;好適には、治療への過程の間に、両方の化合物は、ある特定期間内で少なくとも連続7日投与されることになり − この場合、継続期間は少なくとも7日ということになり;好適には、治療への過程の間に、両方の化合物は、ある特定期間内で少なくとも連続14日投与されることになり − この場合、継続期間は少なくとも14日ということになり;好適には、治療への過程の間に、両方の化合物は、ある特定期間内で少なくとも連続30日投与されることになり − この場合、継続期間は少なくとも30日ということになる。
好適には、治療過程の間、化合物Aおよび化合物Bは、7日間にわたる期間の間で1−4日の特定期間内に投与されることになり、この7日間のうちの他の日の間に化合物Aが単独で投与される。好適には、この7日プロトコルは、2サイクルの間、すなわち14日間;好適には4サイクルの間、すなわち28日間;好適には継続的な投与のために繰り返される。
好適には、化合物Aおよび化合物Bのうちの1つが連続1−30日投与され、そのあと休薬期間があってもよく、そのあと連続1−30日の化合物Aおよび化合物Bのうちの他方の投与が続く。好適には、化合物Aおよび化合物Bのうちの1つが連続2−21日投与され、そのあと休薬期間があってもよく、そのあと連続2−21日の化合物Aおよび化合物Bのうちの他方の投与が続く。好適には、化合物Aおよび化合物Bのうちの1つが連続2−14日投与され、そのあと1−14日の休薬期間が続き、そのあと連続2−14日の化合物Aおよび化合物Bのうちの他方の投与が続く。好適には、化合物Aおよび化合物Bのうちの1つが連続3−7日投与され、そのあと3−10日の休薬期間が続き、そのあと連続3−7日の化合物Aおよび化合物Bのうちの他方の投与が続く。
本発明の組合せ物は、MEKおよび/またはB−Rafの阻害が有益である障害において有用性を有すると考えられる。
免疫療法薬:免疫療法レジメンで使用される薬剤も、式(I)の化合物と組合せて有用であり得る。例えば患者の腫瘍細胞の免疫原性を上昇させるためのex−vivoおよびin−vivoアプローチを含めた免疫療法アプローチ、例えばインターロイキン2、インターロイキン4または顆粒球マクロファージコロニー刺激因子などのサイトカインを用いた形質移入、T細胞の免疫反応不顕性を低下させるためのアプローチ、サイトカインで形質移入した樹状細胞などの形質移入した免疫細胞を使用するアプローチ、サイトカインで形質移入した腫瘍細胞株を使用するアプローチ、および抗イディオタイプ抗体を使用するアプローチ。
異なる変異をコードする複数の起源に由来する癌細胞株についてのBRAFおよびMEK阻害剤のin vitro組合せ物研究
A. 濃度範囲A
薬物組合せ物実験を384穴プレートの中で実施した。細胞を、10% FBSおよび1% ペニシリン/ストレプトマイシンを補った各細胞のタイプに適切な培地の中で500細胞/ウェルで384穴プレートにプレーティングし、37℃、5% CO2で一晩インキュベーションした。各薬物の16の濃度の2倍希釈を、細胞増殖阻害についてマトリクスで試験した。化合物A(遊離形態)について試験した濃度は1μM−0.03nMであり、化合物B(DMSO溶媒和物)については10μM−0.3nMであった。細胞を化合物組合せ物で処置し、37℃で72時間インキュベーションした。製造業者のプロトコルに従ってCellTiter−Glo(登録商標)試薬を使用して細胞成長を測定し、0.5秒読み取りでルミネッセンスモードに設定したPerkinElmer EnVision(商標)読み取り機でシグナルを読み取った。結果は、DMSO処置した細胞と比較した百分率阻害として表され、バックグラウンド補正を、細胞を含有しないウェルからの値を差し引くことにより行った。
Rab>RaおよびRbのうちで高いほうの値の10% = 加成性を超える
Rab<RaおよびRbのうちで高いほうの値の−10% = 拮抗作用
この式を使用して、RabがRaとRbとの間の最も高い値よりも10%以上大きい場合、その薬物組合せ物は加成性を超えると考えられる。RabがRaとRbとの間の最も高い値よりも10%以上小さい場合、その薬物組合せ物は拮抗的である。
セクションAで生成された、しかし臨床的に関連すると見なす(100nM−3nM)薬物濃度についてのみのデータを使用して、化合物Aおよび化合物Bの組合せ物の上記のセクションAに類似の評価を実施した。これらの濃度を、前臨床マウス異種移植モデルで有効であるが無毒である傾向がある濃度として選んだ。これらの濃度を使用して、合計25の薬物組合せ物を各細胞株について評価し、結果を表2に要約する。
方法:
細胞株および成長状態 − ヒト結腸腫瘍株、Colo−205、DLD−1、HCT−8、HT−29、LS−1034、NCI−H508、RKO、SW1417、SW1463、SW480およびSW837、およびヒト黒色腫株A375をATCCから得た。A375PF11はA375由来であった。12R5−1、12R5−3、12R8−1、12R8−3、16R5−2、16R6−3および16R6−4は、1200および1600nMの濃度までの化合物Aの中で成長し、これにより化合物Bに対する獲得された耐性を示すように選択された、A375PF11細胞の混合集団に由来する単一の細胞クローンである。すべての株を、10% ウシ胎仔血清(FBS)を含有するRPMI 1640培地の中で培養した。
CI = Da/IC50(a) + Db/IC50(b) + (Da×Db)/(IC50(a)×IC50(b))
(式中、IC50(a)は化合物AについてのIC50であり、IC50(b)は化合物BについてのIC50であり、Daは、細胞成長の50%を阻害した化合物Bと組合せた化合物Aの濃度であり、Dbは、細胞成長の50%を阻害した化合物Aと組合せた化合物Bの濃度である)とを用いて算出した組合せ指数(Combination Index、CI)を使用して、効力に対する組合せ効果を評価した。一般に、0.9未満、0.9−1.1の間、または>1.1超のCI値は、それぞれ、相乗作用、加成性および拮抗作用を示す。一般に、CI数が小さいほど、相乗作用の強さが大きい。
MEK阻害剤化合物A、BRAF阻害剤化合物Bおよびこれらの組合せ物による細胞増殖阻害の効果を、ヒト腫瘍細胞株のパネルにおいて判定した。(少なくとも2つの独立の実験からの平均IC50)およびIC50での組合せ効果を、BRAFおよびKRAS変異状態とともに表3に要約する。
(1)Chou TC,Talalay P. Quantitative analysis of dose−effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 1984;22:27−55。
A375P F11(BRafV600E変異をコードするヒト黒色腫細胞株)細胞を使用する異種移植モデルを、組織培養液の中で成長させた細胞から確立し、トリプシン消化を使用して無菌的に回収した。この腫瘍細胞を、50%マトリゲルの中の5×106−107細胞で雌の無胸腺マウス(系統 nu/nu)に皮下注射した。腫瘍を確立させた。約200mm3の平均腫瘍体積に対応する移植から24日目に投薬を始めた。
立方mm単位での腫瘍体積=(長さ×幅2)×0.5
を使用して二次元測定値から腫瘍体積を算出した。
A375P細胞を、37℃で5分間、0.25% トリプシン/EDTAに曝露することにより培養フラスコから回収した。剥離した細胞を集め、遠心分離し(1500rpm、5分、4℃)、洗ってトリプシン溶液を除去した。マグネシウムもカルシウムも含まないPBSに細胞を再懸濁させ、数えた。細胞をこれまでのように回転させてPBSを除去し、100μLの皮下注射がマウス1匹あたりに必要とされる細胞数を送達するであろうように、単一の細胞懸濁液を50%マトリゲル:50% PBS(v:v)または100% PBSのいずれかの中で作製した。このA375P黒色腫株を、マウス1匹あたり175万細胞で、8−10週齢の、雌のCD−1 nu/nuマウスに、マトリゲルを用いて皮下注射した。注射後2−4週間以内にすべての細胞株について腫瘍を確立させた(約150−300mm3)。
Claims (12)
- 式(I)の化合物がジメチルスルホキシド溶媒和物の形態にあり、式(II)の化合物がメタンスルホン酸塩の形態にある、請求項1に記載の組合せ物。
- 前記癌が、頭頸部癌、乳癌、肺癌、結腸癌、卵巣癌、前立腺癌、神経膠腫、神経膠芽腫、星状細胞腫、多形神経膠芽腫、バナヤン−ゾナナ症候群、カウデン病、レルミット・デュクロ病、炎症性乳癌、ウィルムス腫瘍、ユーイング肉腫、横紋筋肉腫、上衣腫、髄芽腫、腎癌、肝癌、黒色腫、膵臓癌、肉腫、骨肉腫、骨巨細胞腫、甲状腺癌、リンパ芽球性T細胞白血病、慢性骨髄性白血病、慢性リンパ球性白血病、ヘアリー細胞白血病、急性リンパ芽球性白血病、急性骨髄性白血病、AML、慢性好中球性白血病、急性リンパ芽球性T細胞白血病、形質細胞腫、免疫芽球性大細胞型白血病、マントル細胞白血病、多発性骨髄腫 巨核芽球性白血病、多発性骨髄腫、急性巨核球性白血病、前骨髄球性白血病、赤白血病、悪性リンパ腫、ホジキンリンパ腫、非ホジキンリンパ腫、リンパ芽球性T細胞リンパ腫、バーキットリンパ腫、濾胞性リンパ腫、神経芽細胞腫、膀胱癌、尿路上皮癌、外陰癌、子宮頸癌、子宮内膜癌、腎癌、中皮腫、食道癌、唾液腺癌、肝細胞癌、胃癌、上咽頭癌、頬癌、口腔癌、GIST(消化管間葉性腫瘍)、および精巣癌から選択される、請求項1または2に記載の組合せ物。
- 前記癌が黒色腫である、請求項1または2に記載の組合せ物。
- 請求項1〜4のいずれか1項に記載の組合せ物を含む癌治療用組合せ物キット。
- 癌の治療のための薬剤の製造における、請求項1〜4のいずれか1項に記載の組合せ物の使用。
- 薬学上許容可能な希釈剤または担体と一緒に請求項1〜4のいずれか1項に記載の組合せ物を含む、癌治療用医薬組成物。
- 式(I)の化合物がジメチルスルホキシド溶媒和物の形態にあり、式(II)の化合物がメタンスルホン酸塩の形態にある、請求項8または9に記載の医薬組成物。
- 前記癌が、頭頸部癌、乳癌、肺癌、結腸癌、卵巣癌、前立腺癌、神経膠腫、神経膠芽腫、星状細胞腫、多形神経膠芽腫、バナヤン−ゾナナ症候群、カウデン病、レルミット・デュクロ病、炎症性乳癌、ウィルムス腫瘍、ユーイング肉腫、横紋筋肉腫、上衣腫、髄芽腫、腎癌、肝癌、黒色腫、膵臓癌、肉腫、骨肉腫、骨巨細胞腫、甲状腺癌、リンパ芽球性T細胞白血病、慢性骨髄性白血病、慢性リンパ球性白血病、ヘアリー細胞白血病、急性リンパ芽球性白血病、急性骨髄性白血病、AML、慢性好中球性白血病、急性リンパ芽球性T細胞白血病、形質細胞腫、免疫芽球性大細胞型白血病、マントル細胞白血病、多発性骨髄腫 巨核芽球性白血病、多発性骨髄腫、急性巨核球性白血病、前骨髄球性白血病、赤白血病、悪性リンパ腫、ホジキンリンパ腫、非ホジキンリンパ腫、リンパ芽球性T細胞リンパ腫、バーキットリンパ腫、濾胞性リンパ腫、神経芽細胞腫、膀胱癌、尿路上皮癌、外陰癌、子宮頸癌、子宮内膜癌、腎癌、中皮腫、食道癌、唾液腺癌、肝細胞癌、胃癌、上咽頭癌、頬癌、口腔癌、GIST(消化管間葉性腫瘍)、および精巣癌から選択される、請求項8〜10のいずれか一項に記載の医薬組成物。
- 前記癌が黒色腫である、請求項8〜10のいずれか一項に記載の医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US25221309P | 2009-10-16 | 2009-10-16 | |
US61/252,213 | 2009-10-16 | ||
PCT/US2010/052808 WO2011047238A1 (en) | 2009-10-16 | 2010-10-15 | Combination |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2013508294A JP2013508294A (ja) | 2013-03-07 |
JP5718929B2 true JP5718929B2 (ja) | 2015-05-13 |
Family
ID=43876568
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2012534386A Active JP5718929B2 (ja) | 2009-10-16 | 2010-10-15 | 組合せ物 |
Country Status (33)
Country | Link |
---|---|
US (3) | US8703781B2 (ja) |
EP (3) | EP4159217B1 (ja) |
JP (1) | JP5718929B2 (ja) |
KR (1) | KR101729116B1 (ja) |
CN (1) | CN102655753B (ja) |
AU (1) | AU2010306653B2 (ja) |
BR (1) | BR112012008854B8 (ja) |
CA (1) | CA2775803C (ja) |
CL (1) | CL2012000964A1 (ja) |
CO (1) | CO6531498A2 (ja) |
CR (1) | CR20120155A (ja) |
CY (1) | CY1122013T1 (ja) |
DK (2) | DK3560498T3 (ja) |
DO (1) | DOP2012000091A (ja) |
EA (1) | EA020589B1 (ja) |
ES (2) | ES2930157T3 (ja) |
HR (2) | HRP20221304T1 (ja) |
HU (2) | HUE046139T2 (ja) |
IL (1) | IL219073A (ja) |
LT (2) | LT3560498T (ja) |
MA (1) | MA33746B1 (ja) |
ME (1) | ME03497B (ja) |
MX (1) | MX2012004413A (ja) |
MY (1) | MY174759A (ja) |
NZ (1) | NZ598913A (ja) |
PE (1) | PE20121093A1 (ja) |
PL (2) | PL3560498T3 (ja) |
PT (2) | PT2488033T (ja) |
RS (2) | RS63702B1 (ja) |
SI (1) | SI2488033T1 (ja) |
UA (1) | UA105064C2 (ja) |
WO (1) | WO2011047238A1 (ja) |
ZA (1) | ZA201202612B (ja) |
Families Citing this family (39)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
LT3289876T (lt) | 2008-06-16 | 2022-11-10 | University Of Tennessee Research Foundation | Junginiai, skirti vėžio gydymui |
US9447049B2 (en) | 2010-03-01 | 2016-09-20 | University Of Tennessee Research Foundation | Compounds for treatment of cancer |
US9029408B2 (en) | 2008-06-16 | 2015-05-12 | Gtx, Inc. | Compounds for treatment of cancer |
US11084811B2 (en) | 2010-03-01 | 2021-08-10 | Oncternal Therapeutics, Inc. | Compounds for treatment of cancer |
EA030276B1 (ru) | 2010-03-09 | 2018-07-31 | Дана-Фарбер Кэнсер Инститьют, Инк. | Способы идентификации страдающих раком пациентов и лечения рака у пациентов, у которых имеется или развивается резистентность к первой терапии рака |
JP2014505658A (ja) * | 2010-11-05 | 2014-03-06 | グラクソスミスクライン、インテレクチュアル、プロパティー、ナンバー2、リミテッド | 癌を治療する方法 |
TWI505828B (zh) | 2010-12-20 | 2015-11-01 | 葛蘭素史克智慧財產(第二)有限公司 | 新穎醫藥組成物 |
US9573996B2 (en) | 2011-12-16 | 2017-02-21 | Synthon Biopharmaceuticals B.V. | Monoclonal antibodies to human proinflammatory cytokines and methods for treating inflammatory diseases |
AU2012358999A1 (en) * | 2011-12-22 | 2014-07-10 | Glaxosmithkline Llc | Method of treating cancer with MAGEA3 immunotherapeutic with BRAF inhibitor and/or MEK inhibitor |
US20150126533A1 (en) * | 2012-03-30 | 2015-05-07 | Takeda Pharmaceutical Company Limited | Administration of a raf inhibitor and a mek inhibitor in the treatment of melanoma |
LT2892535T (lt) * | 2012-09-04 | 2021-12-10 | Novartis Ag | Adjuvantinis vėžio gydymo būdas |
CN104812391A (zh) * | 2012-10-25 | 2015-07-29 | 葛兰素史克公司 | 组合 |
PL2925299T3 (pl) * | 2012-11-30 | 2018-11-30 | Novartis Ag | Nowa kompozycja farmaceutyczna |
CN103965170A (zh) * | 2013-01-24 | 2014-08-06 | 通化济达医药有限公司 | 苯磺酰胺吡唑激酶抑制剂 |
CN109568312A (zh) | 2013-03-05 | 2019-04-05 | 田纳西大学研究基金会 | 用于治疗癌症的化合物 |
JP6720075B2 (ja) * | 2013-05-31 | 2020-07-08 | メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. | 癌のための併用療法 |
CN105658206A (zh) * | 2013-06-03 | 2016-06-08 | 诺华股份有限公司 | 抗pd-l1抗体与mek抑制剂和/或braf抑制剂的组合 |
CN104540822B (zh) * | 2013-07-08 | 2016-08-31 | 杭州普晒医药科技有限公司 | 达拉菲尼甲磺酸盐的晶型及其制备方法 |
WO2015059677A1 (en) * | 2013-10-26 | 2015-04-30 | Glaxosmithkline Intellectual Property (No.2) Limited | Methods of treating cancer |
CN103588767B (zh) * | 2013-11-20 | 2016-01-20 | 苏州明锐医药科技有限公司 | 达拉菲尼的制备方法 |
MX2016007653A (es) * | 2013-12-12 | 2016-10-13 | Novartis Ag | Combinaciones de trametinib, panitumumab y dabrafenib para el tratamiento del cancer. |
EP3524694B1 (en) | 2013-12-28 | 2020-07-15 | Guardant Health, Inc. | Methods and systems for detecting genetic variants |
WO2015105822A1 (en) * | 2014-01-07 | 2015-07-16 | Glaxosmithkline Llc | Cancer treatment method |
ES2815374T3 (es) | 2014-05-06 | 2021-03-29 | Oncternal Therapeutics Inc | Compuestos para el tratamiento del cáncer |
KR101629184B1 (ko) | 2014-12-10 | 2016-06-13 | 현대오트론 주식회사 | Autosar 플랫폼에서의 eeprom 처리속도 향상을 위한 주기함수 호출 방법 |
WO2017033113A1 (en) | 2015-08-21 | 2017-03-02 | Acerta Pharma B.V. | Therapeutic combinations of a mek inhibitor and a btk inhibitor |
CA3042697A1 (en) * | 2016-11-03 | 2018-05-11 | The Regents Of The University Of Michigan | Small molecule dual inhibitors of egfr/pi3k and uses thereof |
CN112867803A (zh) | 2018-10-16 | 2021-05-28 | 诺华股份有限公司 | 单独的或与免疫标志物组合的肿瘤突变负荷作为生物标志物用于预测对靶向疗法的应答 |
JP2022526713A (ja) | 2019-03-21 | 2022-05-26 | オンクセオ | がんの処置のための、キナーゼ阻害剤と組み合わせたDbait分子 |
US20220142979A1 (en) * | 2019-07-26 | 2022-05-12 | Ascentage Pharma (Suzhou) Co., Ltd. | Pharmaceutical composition of mdm2 inhibitor and use thereof for preventing and/or treating disease |
EP4054579A1 (en) | 2019-11-08 | 2022-09-14 | Institut National de la Santé et de la Recherche Médicale (INSERM) | Methods for the treatment of cancers that have acquired resistance to kinase inhibitors |
CN114981298A (zh) | 2019-12-12 | 2022-08-30 | 听治疗有限责任公司 | 用于预防和治疗听力损失的组合物和方法 |
WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
US12014835B2 (en) | 2020-02-19 | 2024-06-18 | Vanderbilt University | Methods for evaluating therapeutic benefit of combination therapies |
WO2021168283A1 (en) * | 2020-02-19 | 2021-08-26 | Vanderbilt University | Therapeutic methods and compositions for treating cancer using braf and/or mek inhibitor combination therapy |
JP2024511373A (ja) | 2021-03-18 | 2024-03-13 | ノバルティス アーゲー | がんのためのバイオマーカーおよびその使用 |
IL312469A (en) * | 2021-11-02 | 2024-06-01 | Verastem Inc | Methods for treating abnormal cell proliferation |
WO2023105286A1 (en) | 2021-12-06 | 2023-06-15 | My Personal Therapeutics Ltd | A combination treatment for cancer |
US11873296B2 (en) | 2022-06-07 | 2024-01-16 | Verastem, Inc. | Solid forms of a dual RAF/MEK inhibitor |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5681835A (en) | 1994-04-25 | 1997-10-28 | Glaxo Wellcome Inc. | Non-steroidal ligands for the estrogen receptor |
GB9716557D0 (en) | 1997-08-06 | 1997-10-08 | Glaxo Group Ltd | Benzylidene-1,3-dihydro-indol-2-one derivatives having anti-cancer activity |
AU1529901A (en) * | 1999-11-22 | 2001-06-04 | Smithkline Beecham Plc | Compounds |
DE102004018198A1 (de) * | 2004-04-15 | 2005-11-03 | Merck Patent Gmbh | Sulfonamide |
PL2298768T3 (pl) | 2004-06-11 | 2013-03-29 | Japan Tobacco Inc | Pochodne 5-amino-2,4,7-triokso-3,4,7,8-tetrahydro-2H-pirydo[2,3-d]pirymidyny i związki pokrewne do leczenia nowotworu |
US7378423B2 (en) | 2004-06-11 | 2008-05-27 | Japan Tobacco Inc. | Pyrimidine compound and medical use thereof |
WO2008120004A1 (en) * | 2007-04-02 | 2008-10-09 | Astrazeneca Ab | Combination of a mek- inhibitor and a b-raf inhibitor for the treatment of cancer |
UA99731C2 (ru) | 2007-07-30 | 2012-09-25 | Ардеа Биосайенсис, Инк | Кристаллические полиморфные формы n-(ариламино)сульфонамидов как ингибиторы мэк, композиция (варианты) и применение |
UA103319C2 (en) | 2008-05-06 | 2013-10-10 | Глаксосмитклайн Ллк | Thiazole- and oxazole-benzene sulfonamide compounds |
-
2010
- 2010-10-15 EP EP22189749.9A patent/EP4159217B1/en active Active
- 2010-10-15 SI SI201031933T patent/SI2488033T1/sl unknown
- 2010-10-15 PL PL19174594.2T patent/PL3560498T3/pl unknown
- 2010-10-15 HR HRP20221304TT patent/HRP20221304T1/hr unknown
- 2010-10-15 NZ NZ598913A patent/NZ598913A/xx unknown
- 2010-10-15 ES ES19174594T patent/ES2930157T3/es active Active
- 2010-10-15 AU AU2010306653A patent/AU2010306653B2/en active Active
- 2010-10-15 RS RS20220984A patent/RS63702B1/sr unknown
- 2010-10-15 EP EP19174594.2A patent/EP3560498B1/en active Active
- 2010-10-15 CN CN201080046640.6A patent/CN102655753B/zh active Active
- 2010-10-15 BR BR112012008854A patent/BR112012008854B8/pt active IP Right Grant
- 2010-10-15 HU HUE10824148A patent/HUE046139T2/hu unknown
- 2010-10-15 EA EA201290149A patent/EA020589B1/ru not_active IP Right Cessation
- 2010-10-15 EP EP10824148.0A patent/EP2488033B1/en active Active
- 2010-10-15 DK DK19174594.2T patent/DK3560498T3/da active
- 2010-10-15 PT PT10824148T patent/PT2488033T/pt unknown
- 2010-10-15 PE PE2012000502A patent/PE20121093A1/es active IP Right Grant
- 2010-10-15 LT LTEP19174594.2T patent/LT3560498T/lt unknown
- 2010-10-15 KR KR1020127012649A patent/KR101729116B1/ko active IP Right Grant
- 2010-10-15 RS RSP20191095 patent/RS59181B1/sr unknown
- 2010-10-15 LT LTEP10824148.0T patent/LT2488033T/lt unknown
- 2010-10-15 WO PCT/US2010/052808 patent/WO2011047238A1/en active Application Filing
- 2010-10-15 CA CA2775803A patent/CA2775803C/en active Active
- 2010-10-15 MY MYPI2012001680A patent/MY174759A/en unknown
- 2010-10-15 UA UAA201204675A patent/UA105064C2/uk unknown
- 2010-10-15 HU HUE19174594A patent/HUE060206T2/hu unknown
- 2010-10-15 PL PL10824148T patent/PL2488033T3/pl unknown
- 2010-10-15 US US13/499,779 patent/US8703781B2/en active Active
- 2010-10-15 PT PT191745942T patent/PT3560498T/pt unknown
- 2010-10-15 DK DK10824148.0T patent/DK2488033T3/da active
- 2010-10-15 ES ES10824148T patent/ES2745479T3/es active Active
- 2010-10-15 ME MEP-2019-236A patent/ME03497B/me unknown
- 2010-10-15 MX MX2012004413A patent/MX2012004413A/es active IP Right Grant
- 2010-10-15 JP JP2012534386A patent/JP5718929B2/ja active Active
-
2012
- 2012-03-27 CR CR20120155A patent/CR20120155A/es unknown
- 2012-04-03 DO DO2012000091A patent/DOP2012000091A/es unknown
- 2012-04-05 IL IL219073A patent/IL219073A/en active IP Right Grant
- 2012-04-11 ZA ZA2012/02612A patent/ZA201202612B/en unknown
- 2012-04-16 CL CL2012000964A patent/CL2012000964A1/es unknown
- 2012-04-27 CO CO12069732A patent/CO6531498A2/es active IP Right Grant
- 2012-05-11 MA MA34863A patent/MA33746B1/fr unknown
-
2014
- 2014-03-05 US US14/197,421 patent/US8952018B2/en active Active
- 2014-12-22 US US14/578,804 patent/US20150111904A1/en not_active Abandoned
-
2019
- 2019-09-06 HR HRP20191617 patent/HRP20191617T1/hr unknown
- 2019-09-09 CY CY20191100943T patent/CY1122013T1/el unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5718929B2 (ja) | 組合せ物 | |
AU2013334599B2 (en) | Combination | |
JP2017500307A (ja) | がんの処置のためのトラメチニブ、パニツムマブおよびダブラフェニブの組合せ | |
JP6563558B2 (ja) | 組み合わせ薬物療法 | |
JP6355724B2 (ja) | がんを治療するためのアフレセルチブと組み合わせたエンザルタミド | |
JP2021155446A (ja) | 組合せ物 | |
JP6185839B2 (ja) | Braf阻害薬とvegf阻害薬との組み合わせ | |
JP2017507963A (ja) | Btk阻害薬とakt阻害薬を含む組み合わせ |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20130422 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20140527 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140821 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20150310 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20150319 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5718929 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R153 | Grant of patent term extension |
Free format text: JAPANESE INTERMEDIATE CODE: R153 |
|
R153 | Grant of patent term extension |
Free format text: JAPANESE INTERMEDIATE CODE: R153 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R153 | Grant of patent term extension |
Free format text: JAPANESE INTERMEDIATE CODE: R153 |
|
R153 | Grant of patent term extension |
Free format text: JAPANESE INTERMEDIATE CODE: R153 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R153 | Grant of patent term extension |
Free format text: JAPANESE INTERMEDIATE CODE: R153 |
|
R153 | Grant of patent term extension |
Free format text: JAPANESE INTERMEDIATE CODE: R153 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |