AU2013230146B2 - 2-amino, 6-phenyl substituted pyrido [2, 3 - d] pyrimidine derivatives useful as Raf kinase inhibitors - Google Patents
2-amino, 6-phenyl substituted pyrido [2, 3 - d] pyrimidine derivatives useful as Raf kinase inhibitors Download PDFInfo
- Publication number
- AU2013230146B2 AU2013230146B2 AU2013230146A AU2013230146A AU2013230146B2 AU 2013230146 B2 AU2013230146 B2 AU 2013230146B2 AU 2013230146 A AU2013230146 A AU 2013230146A AU 2013230146 A AU2013230146 A AU 2013230146A AU 2013230146 B2 AU2013230146 B2 AU 2013230146B2
- Authority
- AU
- Australia
- Prior art keywords
- raf
- cancer
- methyl
- atcc
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 102000009929 raf Kinases Human genes 0.000 title description 5
- 108010077182 raf Kinases Proteins 0.000 title description 5
- 229940043355 kinase inhibitor Drugs 0.000 title description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 3
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 title description 2
- 159000000018 pyrido[2,3-d]pyrimidines Chemical class 0.000 title description 2
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 87
- 150000001875 compounds Chemical class 0.000 claims abstract description 85
- 201000011510 cancer Diseases 0.000 claims abstract description 64
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims description 47
- 201000001441 melanoma Diseases 0.000 claims description 46
- HHCBMISMPSAZBF-UHFFFAOYSA-N LY3009120 Chemical compound CC1=NC2=NC(NC)=NC=C2C=C1C1=CC(NC(=O)NCCC(C)(C)C)=C(F)C=C1C HHCBMISMPSAZBF-UHFFFAOYSA-N 0.000 claims description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 17
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 16
- 206010009944 Colon cancer Diseases 0.000 claims description 14
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 14
- 206010033128 Ovarian cancer Diseases 0.000 claims description 11
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 11
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 10
- 201000002510 thyroid cancer Diseases 0.000 claims description 10
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 7
- KXVGTQFNYXBBHD-UHFFFAOYSA-N ethenyl acetate;pyrrolidin-2-one Chemical compound CC(=O)OC=C.O=C1CCCN1 KXVGTQFNYXBBHD-UHFFFAOYSA-N 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 claims description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 abstract description 18
- 239000004202 carbamide Substances 0.000 abstract description 10
- 101100381978 Mus musculus Braf gene Proteins 0.000 description 138
- 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 136
- 210000004027 cell Anatomy 0.000 description 103
- 230000035772 mutation Effects 0.000 description 100
- 102200055464 rs113488022 Human genes 0.000 description 73
- 239000000203 mixture Substances 0.000 description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- 230000000694 effects Effects 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 46
- 239000007787 solid Substances 0.000 description 45
- 238000003556 assay Methods 0.000 description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 238000003756 stirring Methods 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 33
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 32
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 32
- 230000005764 inhibitory process Effects 0.000 description 27
- 101710113436 GTPase KRas Proteins 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 26
- 230000037361 pathway Effects 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- 102100039788 GTPase NRas Human genes 0.000 description 23
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 23
- 239000003112 inhibitor Substances 0.000 description 23
- 108090000623 proteins and genes Proteins 0.000 description 22
- 230000004913 activation Effects 0.000 description 21
- 102000016914 ras Proteins Human genes 0.000 description 21
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 21
- 229960003862 vemurafenib Drugs 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 235000019439 ethyl acetate Nutrition 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 19
- 108010014186 ras Proteins Proteins 0.000 description 19
- 238000012360 testing method Methods 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- 239000007962 solid dispersion Substances 0.000 description 18
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 17
- 238000005481 NMR spectroscopy Methods 0.000 description 17
- 239000003814 drug Substances 0.000 description 17
- 238000001914 filtration Methods 0.000 description 17
- 230000002401 inhibitory effect Effects 0.000 description 17
- 230000004663 cell proliferation Effects 0.000 description 16
- 239000012141 concentrate Substances 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- -1 C-Raf Proteins 0.000 description 15
- 102000043136 MAP kinase family Human genes 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 108091054455 MAP kinase family Proteins 0.000 description 14
- 229940079593 drug Drugs 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- 210000004881 tumor cell Anatomy 0.000 description 14
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 13
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 13
- 101150019464 ARAF gene Proteins 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- 239000000523 sample Substances 0.000 description 12
- 108010091528 Proto-Oncogene Proteins B-raf Proteins 0.000 description 11
- 102000018471 Proto-Oncogene Proteins B-raf Human genes 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 10
- 230000036210 malignancy Effects 0.000 description 10
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 10
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 10
- 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 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 9
- 238000012054 celltiter-glo Methods 0.000 description 9
- 238000007824 enzymatic assay Methods 0.000 description 9
- 239000001963 growth medium Substances 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 9
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 9
- 238000001262 western blot Methods 0.000 description 9
- 108060006687 MAP kinase kinase kinase Proteins 0.000 description 8
- 108091000080 Phosphotransferase Proteins 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000001516 cell proliferation assay Methods 0.000 description 8
- 230000003833 cell viability Effects 0.000 description 8
- 230000007246 mechanism Effects 0.000 description 8
- 230000002018 overexpression Effects 0.000 description 8
- 230000000803 paradoxical effect Effects 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 102000020233 phosphotransferase Human genes 0.000 description 8
- 238000013207 serial dilution Methods 0.000 description 8
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 8
- YZDJQTHVDDOVHR-UHFFFAOYSA-N PLX-4720 Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(Cl)=CN=C3NC=2)=C1F YZDJQTHVDDOVHR-UHFFFAOYSA-N 0.000 description 7
- 108010029485 Protein Isoforms Proteins 0.000 description 7
- 102000001708 Protein Isoforms Human genes 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 230000014509 gene expression Effects 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- 230000019491 signal transduction Effects 0.000 description 7
- 230000011664 signaling Effects 0.000 description 7
- 230000035899 viability Effects 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- 208000031404 Chromosome Aberrations Diseases 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000001594 aberrant effect Effects 0.000 description 6
- 230000003213 activating effect Effects 0.000 description 6
- 238000013019 agitation Methods 0.000 description 6
- 231100000673 dose–response relationship Toxicity 0.000 description 6
- 239000012091 fetal bovine serum Substances 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 6
- 230000002068 genetic effect Effects 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- 210000004072 lung Anatomy 0.000 description 6
- DTBNBXWJWCWCIK-UHFFFAOYSA-K phosphonatoenolpyruvate Chemical compound [O-]C(=O)C(=C)OP([O-])([O-])=O DTBNBXWJWCWCIK-UHFFFAOYSA-K 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 5
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 5
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 5
- 229930182816 L-glutamine Natural products 0.000 description 5
- 229940124647 MEK inhibitor Drugs 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 108700020796 Oncogene Proteins 0.000 description 5
- 229930182555 Penicillin Natural products 0.000 description 5
- 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 5
- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 230000001028 anti-proliverative effect Effects 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 231100000005 chromosome aberration Toxicity 0.000 description 5
- 238000006471 dimerization reaction Methods 0.000 description 5
- 230000005284 excitation Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 208000020816 lung neoplasm Diseases 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 229940049954 penicillin Drugs 0.000 description 5
- 229930029653 phosphoenolpyruvate Natural products 0.000 description 5
- 230000007420 reactivation Effects 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229960005322 streptomycin Drugs 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 230000004614 tumor growth Effects 0.000 description 5
- BFNHXYBUOCXLSH-UHFFFAOYSA-N 1-(3,3-dimethylbutyl)-3-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea Chemical compound CC1=CC(F)=C(NC(=O)NCCC(C)(C)C)C=C1B1OC(C)(C)C(C)(C)O1 BFNHXYBUOCXLSH-UHFFFAOYSA-N 0.000 description 4
- GSWRZGWQZUJSNC-UHFFFAOYSA-N 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound CC1=CC(F)=C(N)C=C1B1OC(C)(C)C(C)(C)O1 GSWRZGWQZUJSNC-UHFFFAOYSA-N 0.000 description 4
- FGONQMFYFJRAIG-UHFFFAOYSA-N 4-amino-2-methylsulfanylpyrimidine-5-carbaldehyde Chemical compound CSC1=NC=C(C=O)C(N)=N1 FGONQMFYFJRAIG-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 208000005623 Carcinogenesis Diseases 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 4
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 4
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 4
- 229910010082 LiAlH Inorganic materials 0.000 description 4
- 206010064912 Malignant transformation Diseases 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 101000957678 Mus musculus Cytochrome P450 7B1 Proteins 0.000 description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 102000013009 Pyruvate Kinase Human genes 0.000 description 4
- 108020005115 Pyruvate Kinase Proteins 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 101000957679 Rattus norvegicus 25-hydroxycholesterol 7-alpha-hydroxylase Proteins 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 230000036952 cancer formation Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 231100000504 carcinogenesis Toxicity 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 230000007783 downstream signaling Effects 0.000 description 4
- QINRQIZOBCQKAZ-UHFFFAOYSA-N ethyl 4-amino-2-methylsulfanylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(SC)N=C1N QINRQIZOBCQKAZ-UHFFFAOYSA-N 0.000 description 4
- XLSMFKSTNGKWQX-UHFFFAOYSA-N hydroxyacetone Chemical compound CC(=O)CO XLSMFKSTNGKWQX-UHFFFAOYSA-N 0.000 description 4
- 201000007270 liver cancer Diseases 0.000 description 4
- 208000014018 liver neoplasm Diseases 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 239000006166 lysate Substances 0.000 description 4
- 230000036212 malign transformation Effects 0.000 description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- MAWJVEMYTLZRFJ-UHFFFAOYSA-N n-(3,3-dimethylbutyl)-1-phenylmethanimine Chemical compound CC(C)(C)CCN=CC1=CC=CC=C1 MAWJVEMYTLZRFJ-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 230000002611 ovarian Effects 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 201000002528 pancreatic cancer Diseases 0.000 description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 description 4
- 230000003285 pharmacodynamic effect Effects 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000012552 review Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- 238000011144 upstream manufacturing Methods 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- 231100000747 viability assay Toxicity 0.000 description 4
- 238000003026 viability measurement method Methods 0.000 description 4
- KSOYQIUBKFMXOE-UHFFFAOYSA-N (7-methyl-2-methylsulfanylpyrido[2,3-d]pyrimidin-6-yl) trifluoromethanesulfonate Chemical compound C1=C(OS(=O)(=O)C(F)(F)F)C(C)=NC2=NC(SC)=NC=C21 KSOYQIUBKFMXOE-UHFFFAOYSA-N 0.000 description 3
- VMXDJIHJOUZBAW-UHFFFAOYSA-N 1-bromo-4-fluoro-2-methyl-5-nitrobenzene Chemical compound CC1=CC(F)=C([N+]([O-])=O)C=C1Br VMXDJIHJOUZBAW-UHFFFAOYSA-N 0.000 description 3
- VPENPNZYTNWJNP-UHFFFAOYSA-N 5-bromo-2-fluoro-4-methylaniline Chemical compound CC1=CC(F)=C(N)C=C1Br VPENPNZYTNWJNP-UHFFFAOYSA-N 0.000 description 3
- FTVXKEIBWFHBIF-UHFFFAOYSA-N 7-methyl-2-methylsulfanylpyrido[2,3-d]pyrimidin-6-ol Chemical compound C1=C(O)C(C)=NC2=NC(SC)=NC=C21 FTVXKEIBWFHBIF-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 206010069754 Acquired gene mutation Diseases 0.000 description 3
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 3
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 3
- 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 Proteins 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 108010002386 Interleukin-3 Proteins 0.000 description 3
- 239000005909 Kieselgur Substances 0.000 description 3
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 3
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 3
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 101710141955 RAF proto-oncogene serine/threonine-protein kinase Proteins 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 208000033781 Thyroid carcinoma Diseases 0.000 description 3
- ZQAMRSXFXKKLOW-UHFFFAOYSA-N [7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl] trifluoromethanesulfonate Chemical compound C1=C(OS(=O)(=O)C(F)(F)F)C(C)=NC2=NC(NC)=NC=C21 ZQAMRSXFXKKLOW-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 230000033115 angiogenesis Effects 0.000 description 3
- 230000003466 anti-cipated effect Effects 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 210000001072 colon Anatomy 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 230000002559 cytogenic effect Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 201000005787 hematologic cancer Diseases 0.000 description 3
- 239000012456 homogeneous solution Substances 0.000 description 3
- 102000050152 human BRAF Human genes 0.000 description 3
- 239000012139 lysis buffer Substances 0.000 description 3
- 208000025113 myeloid leukemia Diseases 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 description 3
- 102200124924 rs11554290 Human genes 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 230000037439 somatic mutation Effects 0.000 description 3
- 210000000130 stem cell Anatomy 0.000 description 3
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 3
- 230000009750 upstream signaling Effects 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- 239000012130 whole-cell lysate Substances 0.000 description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- RJPNVPITBYXBNB-UHFFFAOYSA-N 1-bromo-4-fluoro-2-methylbenzene Chemical compound CC1=CC(F)=CC=C1Br RJPNVPITBYXBNB-UHFFFAOYSA-N 0.000 description 2
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- GPWHFPWZAPOYNO-UHFFFAOYSA-N 3,3-dimethylbutan-1-amine Chemical compound CC(C)(C)CCN GPWHFPWZAPOYNO-UHFFFAOYSA-N 0.000 description 2
- 108091006112 ATPases Proteins 0.000 description 2
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 2
- 241000283725 Bos Species 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- 229910016523 CuKa Inorganic materials 0.000 description 2
- 101000876610 Dictyostelium discoideum Extracellular signal-regulated kinase 2 Proteins 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 102100023266 Dual specificity mitogen-activated protein kinase kinase 2 Human genes 0.000 description 2
- 101710146529 Dual specificity mitogen-activated protein kinase kinase 2 Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000018898 GTPase-Activating Proteins Human genes 0.000 description 2
- 108091006094 GTPase-accelerating proteins Proteins 0.000 description 2
- 108010070675 Glutathione transferase Proteins 0.000 description 2
- 102100029100 Hematopoietic prostaglandin D synthase Human genes 0.000 description 2
- 101001052493 Homo sapiens Mitogen-activated protein kinase 1 Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 238000003728 KiNativ assay Methods 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 2
- 102100026907 Mitogen-activated protein kinase kinase kinase 8 Human genes 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 102000001253 Protein Kinase Human genes 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
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000002518 antifoaming agent Substances 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 210000000349 chromosome Anatomy 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000013480 data collection Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000002050 diffraction method Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 230000004049 epigenetic modification Effects 0.000 description 2
- SNNHLSHDDGJVDM-UHFFFAOYSA-N ethyl 4-chloro-2-methylsulfanylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(SC)N=C1Cl SNNHLSHDDGJVDM-UHFFFAOYSA-N 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 2
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 2
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 2
- 238000003119 immunoblot Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 201000005296 lung carcinoma Diseases 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- GPGYYWQDCFNVOU-UHFFFAOYSA-N n,7-dimethylpyrido[2,3-d]pyrimidin-2-amine Chemical compound C1=CC(C)=NC2=NC(NC)=NC=C21 GPGYYWQDCFNVOU-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 210000004940 nucleus Anatomy 0.000 description 2
- 231100000590 oncogenic Toxicity 0.000 description 2
- 230000002246 oncogenic effect Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 238000003752 polymerase chain reaction Methods 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- FIWVEQLUJUBBPG-UHFFFAOYSA-N prop-1-en-2-yl n-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate Chemical compound C1=C(F)C(NC(=O)OC(=C)C)=CC(B2OC(C)(C)C(C)(C)O2)=C1C FIWVEQLUJUBBPG-UHFFFAOYSA-N 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 229940054269 sodium pyruvate Drugs 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 101150084750 1 gene Proteins 0.000 description 1
- MMZYCBHLNZVROM-UHFFFAOYSA-N 1-fluoro-2-methylbenzene Chemical compound CC1=CC=CC=C1F MMZYCBHLNZVROM-UHFFFAOYSA-N 0.000 description 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- CWISRCWPFJNOGM-UHFFFAOYSA-N 3,3-dimethylbutan-1-amine;hydrochloride Chemical compound Cl.CC(C)(C)CCN CWISRCWPFJNOGM-UHFFFAOYSA-N 0.000 description 1
- LTNUSYNQZJZUSY-UHFFFAOYSA-N 3,3-dimethylbutanal Chemical compound CC(C)(C)CC=O LTNUSYNQZJZUSY-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- ODQDPHCCNTZQJZ-UHFFFAOYSA-N 4,5-dimethylpyrido[2,3-d]pyrimidin-2-amine Chemical compound CC1=CC=NC=2N=C(N=C(C=21)C)N ODQDPHCCNTZQJZ-UHFFFAOYSA-N 0.000 description 1
- VXIPPNFZDKMJAD-UHFFFAOYSA-N 6-bromo-n,7-dimethylpyrido[2,3-d]pyrimidin-2-amine Chemical compound C1=C(Br)C(C)=NC2=NC(NC)=NC=C21 VXIPPNFZDKMJAD-UHFFFAOYSA-N 0.000 description 1
- KHUJRQVZQMZLKS-UHFFFAOYSA-N 7-methyl-2-methylsulfanylpyrido[2,3-d]pyrimidine Chemical compound C1=CC(C)=NC2=NC(SC)=NC=C21 KHUJRQVZQMZLKS-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 101100455868 Arabidopsis thaliana MKK2 gene Proteins 0.000 description 1
- 102000016605 B-Cell Activating Factor Human genes 0.000 description 1
- 108010028006 B-Cell Activating Factor Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 229940124204 C-kit inhibitor Drugs 0.000 description 1
- 101100165177 Caenorhabditis elegans bath-15 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 238000003734 CellTiter-Glo Luminescent Cell Viability Assay Methods 0.000 description 1
- 208000016718 Chromosome Inversion Diseases 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- 230000007067 DNA methylation Effects 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 102100030013 Endoribonuclease Human genes 0.000 description 1
- 101710199605 Endoribonuclease Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- PSVXHNORKYFWAO-UHFFFAOYSA-N FC1=C(C=C(C(=C1)C)C1=CC2=C(N=C(N=C2)NC)N=C1C)NC(=O)N Chemical compound FC1=C(C=C(C(=C1)C)C1=CC2=C(N=C(N=C2)NC)N=C1C)NC(=O)N PSVXHNORKYFWAO-UHFFFAOYSA-N 0.000 description 1
- 102000013446 GTP Phosphohydrolases Human genes 0.000 description 1
- 108091006109 GTPases Proteins 0.000 description 1
- 208000034951 Genetic Translocation Diseases 0.000 description 1
- 208000031448 Genomic Instability 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
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001008874 Homo sapiens Mast/stem cell growth factor receptor Kit Proteins 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 101150010110 Map3k8 gene Proteins 0.000 description 1
- 102100027754 Mast/stem cell growth factor receptor Kit Human genes 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 229910019093 NaOCl Inorganic materials 0.000 description 1
- 102000048850 Neoplasm Genes Human genes 0.000 description 1
- 108700019961 Neoplasm Genes Proteins 0.000 description 1
- 102000007530 Neurofibromin 1 Human genes 0.000 description 1
- 108010085793 Neurofibromin 1 Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 239000006057 Non-nutritive feed additive Substances 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920003072 Plasdone™ povidone Polymers 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 229940123690 Raf kinase inhibitor Drugs 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 1
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 238000003016 alphascreen Methods 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- 230000003127 anti-melanomic effect Effects 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003491 array Methods 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 201000009036 biliary tract cancer Diseases 0.000 description 1
- 208000020790 biliary tract neoplasm Diseases 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 239000007844 bleaching agent Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- JJWKPURADFRFRB-UHFFFAOYSA-N carbonyl sulfide Chemical compound O=C=S JJWKPURADFRFRB-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 108020001778 catalytic domains Proteins 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000010307 cell transformation Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 208000037516 chromosome inversion disease Diseases 0.000 description 1
- 210000001726 chromosome structure Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 230000002074 deregulated effect Effects 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000002357 endometrial effect Effects 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
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000003090 exacerbative effect Effects 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000006650 fundamental cellular process Effects 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 231100000118 genetic alteration Toxicity 0.000 description 1
- 230000004077 genetic alteration Effects 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 1
- 239000011544 gradient gel Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 238000009474 hot melt extrusion Methods 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000013394 immunophenotyping Methods 0.000 description 1
- 238000007901 in situ hybridization Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000005040 ion trap Methods 0.000 description 1
- 150000002500 ions Chemical group 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
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 210000002752 melanocyte Anatomy 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
- 230000009401 metastasis Effects 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229940125374 mitogen-activated extracellular signal-regulated kinase inhibitor Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 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
- STECCGVGUYBWAZ-UHFFFAOYSA-N n-benzyl-3,3-dimethylbutan-1-imine Chemical compound CC(C)(C)CC=NCC1=CC=CC=C1 STECCGVGUYBWAZ-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 102000051624 phosphatidylethanolamine binding protein Human genes 0.000 description 1
- 108700021017 phosphatidylethanolamine binding protein Proteins 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920002959 polymer blend Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- AMMGCGVWJMRTQI-UHFFFAOYSA-N prop-1-en-2-yl carbonochloridate Chemical compound CC(=C)OC(Cl)=O AMMGCGVWJMRTQI-UHFFFAOYSA-N 0.000 description 1
- 239000003531 protein hydrolysate Substances 0.000 description 1
- 229940076788 pyruvate Drugs 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 231100000161 signs of toxicity Toxicity 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000030968 tissue homeostasis Effects 0.000 description 1
- 230000002463 transducing effect Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000003151 transfection method Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261607702P | 2012-03-07 | 2012-03-07 | |
| US61/607,702 | 2012-03-07 | ||
| PCT/US2013/029084 WO2013134243A1 (en) | 2012-03-07 | 2013-03-05 | 2-amino, 6-phenyl substituted pyrido [2, 3 - d] pyrimidine derivatives useful as raf kinase inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2013230146A1 AU2013230146A1 (en) | 2014-08-14 |
| AU2013230146B2 true AU2013230146B2 (en) | 2015-09-10 |
Family
ID=47884613
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2013230146A Ceased AU2013230146B2 (en) | 2012-03-07 | 2013-03-05 | 2-amino, 6-phenyl substituted pyrido [2, 3 - d] pyrimidine derivatives useful as Raf kinase inhibitors |
Country Status (39)
Families Citing this family (71)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR090151A1 (es) * | 2012-03-07 | 2014-10-22 | Lilly Co Eli | Compuestos inhibidores de raf |
| US8461179B1 (en) | 2012-06-07 | 2013-06-11 | Deciphera Pharmaceuticals, Llc | Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases |
| TWI704151B (zh) | 2014-12-22 | 2020-09-11 | 美商美國禮來大藥廠 | Ｅｒｋ抑制劑 |
| CA3026876A1 (en) * | 2016-06-10 | 2017-12-14 | Novartis Ag | Therapeutic uses of a c-raf inhibitor |
| EP3558979B1 (en) | 2016-12-22 | 2021-02-17 | Boehringer Ingelheim International GmbH | Novel benzylamino substituted quinazolines and derivatives as sos1 inhibitors |
| AU2018258581A1 (en) * | 2017-04-28 | 2019-11-07 | Quartz Therapeutics, Inc. | RAF-degrading conjugate compounds |
| HRP20230400T1 (hr) | 2017-12-21 | 2023-06-23 | Boehringer Ingelheim International Gmbh | Benzilamino supstituirani piridopirimidinoni i derivati kao inhibitori sos1 |
| JP7161849B2 (ja) * | 2018-01-24 | 2022-10-27 | 株式会社クラレ | 第一級アミンの製造方法 |
| CN118416236A (zh) | 2018-01-31 | 2024-08-02 | 德西费拉制药有限责任公司 | 治疗胃肠道间质瘤的组合疗法 |
| IL276398B2 (en) | 2018-01-31 | 2026-03-01 | Deciphera Pharmaceuticals Llc | Combination therapy for mastocytosis |
| JP2022500385A (ja) | 2018-09-10 | 2022-01-04 | ミラティ セラピューティクス， インコーポレイテッド | 組み合わせ療法 |
| BR112021012812A2 (pt) | 2018-12-28 | 2021-12-07 | Deciphera Pharmaceuticals Llc | Csf1r inhibitors para uso e tratamento de câncer |
| HRP20240012T1 (hr) | 2019-02-06 | 2024-03-29 | Eli Lilly And Company | Derivati 1-((2-(2,2,2-trifluoroetoksi)piridin-4-il)metil)uree kao kcnq potencijatori |
| AR118119A1 (es) * | 2019-02-18 | 2021-09-22 | Genentech Inc | Compuestos de pirido-pirimidinilo y métodos de uso |
| WO2020185812A1 (en) | 2019-03-11 | 2020-09-17 | Teva Pharmaceuticals International Gmbh | Solid state forms of ripretinib |
| TW202106684A (zh) | 2019-05-03 | 2021-02-16 | 美商奇奈特生物製藥公司 | Raf激酶抑制劑 |
| US11518758B2 (en) | 2019-05-10 | 2022-12-06 | Deciphera Pharmaceuticals, Llc | Heteroarylaminopyrimidine amide autophagy inhibitors and methods of use thereof |
| PE20220597A1 (es) | 2019-05-10 | 2022-04-22 | Deciphera Pharmaceuticals Llc | Inhibidores de la autofagia de fenilaminopirimidina amida y metodos de uso de estos |
| PE20221083A1 (es) | 2019-06-17 | 2022-07-05 | Deciphera Pharmaceuticals Llc | Inhibidores de la autofagia de la amida aminopirimidina y sus metodos de uso |
| EP4013412B1 (en) | 2019-08-12 | 2026-01-28 | Deciphera Pharmaceuticals, LLC | Ripretinib for treating gastrointestinal stromal tumors |
| TWI878335B (zh) | 2019-08-12 | 2025-04-01 | 美商迪賽孚爾製藥有限公司 | 治療胃腸道基質瘤方法 |
| JP7626910B2 (ja) | 2019-10-24 | 2025-02-05 | ピエール ファーブル メディカモン | Ｒａｆキナーゼの阻害剤 |
| MX2022008103A (es) | 2019-12-30 | 2022-09-19 | Deciphera Pharmaceuticals Llc | Formulaciones de inhibidores de la cinasa amorfa y metodos de estas. |
| EP4084779B1 (en) | 2019-12-30 | 2024-10-09 | Deciphera Pharmaceuticals, LLC | Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea |
| JP7808058B2 (ja) | 2020-06-02 | 2026-01-28 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | がんを治療するための縮合環化２－アミノ－３－シアノチオフェン及び誘導体 |
| WO2022060996A1 (en) | 2020-09-18 | 2022-03-24 | Kinnate Biopharma Inc. | Inhibitors of raf kinases |
| WO2022081469A1 (en) | 2020-10-12 | 2022-04-21 | Kinnate Biopharma Inc. | Inhibitors of raf kinases |
| US12064421B2 (en) | 2020-11-02 | 2024-08-20 | Boehringer Ingelheim International Gmbh | Substituted 1H-pyrazolo[4,3-c]pyridines and derivatives as EGFR inhibitors |
| IL302807A (en) | 2020-11-18 | 2023-07-01 | Deciphera Pharmaceuticals Llc | Gcn2 and perk kinase inhibitors and methods of use thereof |
| JP7849366B2 (ja) | 2020-12-22 | 2026-04-21 | キル・レガー・セラピューティクス・インコーポレーテッド | Ｓｏｓ１阻害剤およびその使用 |
| BR112023021913A2 (pt) | 2021-04-23 | 2024-01-16 | Kinnate Biopharma Inc | Tratamento de câncer com inibidor de raf |
| US12065427B2 (en) | 2021-04-29 | 2024-08-20 | Boehringer Ingelheim International Gmbh | Heterocyclic compounds capable of activating STING |
| JP2024542692A (ja) | 2021-12-01 | 2024-11-15 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 環化２－アミノ－３－シアノチオフェンを含むｋｒａ分解化合物 |
| JP2024543976A (ja) | 2021-12-01 | 2024-11-26 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 癌の処置のための環化２－アミノ－３－シアノチオフェン及び誘導体 |
| CN118574835A (zh) | 2021-12-01 | 2024-08-30 | 勃林格殷格翰国际有限公司 | 用于治疗癌症的环状2-氨基-3-氰基噻吩及衍生物 |
| WO2023099624A1 (en) | 2021-12-01 | 2023-06-08 | Boehringer Ingelheim International Gmbh | Annulated 2-amino-3-cyano thiophenes and derivatives for the treatment of cancer |
| TW202340208A (zh) | 2021-12-01 | 2023-10-16 | 德商百靈佳殷格翰國際股份有限公司 | 用於治療癌症之環狀2-胺基-3-氰基噻吩及衍生物 |
| WO2023099608A1 (en) | 2021-12-01 | 2023-06-08 | Boehringer Ingelheim International Gmbh | Annulated 2-amino-3-cyano thiophenes and derivatives for the treatment of cancer |
| PE20250609A1 (es) | 2021-12-03 | 2025-02-26 | Deciphera Pharmaceuticals Llc | Inhibidores de gcn2 y perk quinasa y metodos de uso de los mismos |
| CA3240263A1 (en) | 2021-12-09 | 2023-06-15 | Daniel L. Flynn | Raf kinase inhibitors and methods of use thereof |
| CA3240192A1 (en) | 2021-12-09 | 2023-06-15 | Daniel L. Flynn | Raf kinase inhibitors and methods of use thereof |
| JP2025501744A (ja) | 2021-12-23 | 2025-01-23 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 脳浸透性ｓｏｓ１阻害剤としての８－アザキナゾリン |
| WO2023173017A1 (en) * | 2022-03-09 | 2023-09-14 | Blossomhill Therapeutics, Inc. | Kras inhibitors for treating disease |
| US11779572B1 (en) | 2022-09-02 | 2023-10-10 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
| WO2024089006A1 (en) | 2022-10-26 | 2024-05-02 | Boehringer Ingelheim International Gmbh | Heterocyclic compounds capable of activating sting |
| JP2026512969A (ja) | 2022-10-26 | 2026-04-22 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Ｓｔｉｎｇを活性化することができる複素環式化合物 |
| CA3266173A1 (en) | 2022-10-26 | 2024-05-02 | Boehringer Ingelheim International Gmbh | HETEROCYCLIC COMPOUNDS CAPABLE OF ACTIVATING STING |
| TW202508595A (zh) | 2023-05-04 | 2025-03-01 | 美商銳新醫藥公司 | 用於ｒａｓ相關疾病或病症之組合療法 |
| WO2024246099A1 (en) | 2023-05-30 | 2024-12-05 | Boehringer Ingelheim International Gmbh | Spirocyclic annulated 2-amino-3-cyano thiophenes and derivatives for the treatment of cancer |
| GB2631397A (en) | 2023-06-28 | 2025-01-08 | Sevenless Therapeutics Ltd | New treatments for pain |
| US20250049810A1 (en) | 2023-08-07 | 2025-02-13 | Revolution Medicines, Inc. | Methods of treating a ras protein-related disease or disorder |
| GB2633813A (en) | 2023-09-21 | 2025-03-26 | Sevenless Therapeutics Ltd | New treatments for pain |
| AU2024360465A1 (en) | 2023-10-12 | 2026-04-09 | Revolution Medicines, Inc. | Macrocyclic ras inhibitors |
| WO2025083426A1 (en) | 2023-10-20 | 2025-04-24 | Sevenless Therapeutics Limited | New treatments for pain |
| US20250206720A1 (en) | 2023-12-08 | 2025-06-26 | Deciphera Pharmaceuticals, Llc | Solid forms of an ulk inhibitor |
| WO2025122952A1 (en) | 2023-12-08 | 2025-06-12 | Deciphera Pharmaceuticals, Llc | Formulations of vimseltinib |
| TW202542151A (zh) | 2023-12-22 | 2025-11-01 | 美商銳格醫藥有限公司 | Ｓｏｓ１抑制劑及其用途 |
| WO2025146548A1 (en) | 2024-01-04 | 2025-07-10 | Sevenless Therapeutics Limited | Sos1 inhibitors useful to treat pain and cancer |
| WO2025171296A1 (en) | 2024-02-09 | 2025-08-14 | Revolution Medicines, Inc. | Ras inhibitors |
| US20250313560A1 (en) | 2024-04-03 | 2025-10-09 | Boehringer Ingelheim International Gmbh | Novel bicyclic benzylamido pyridine derivatives as SOS1 inhibitors |
| WO2025231106A1 (en) | 2024-05-01 | 2025-11-06 | Deciphera Pharmaceuticals, Llc | Csf-1r inhibitors and methods of use thereof |
| TW202547461A (zh) | 2024-05-17 | 2025-12-16 | 美商銳新醫藥公司 | Ｒａｓ抑制劑 |
| WO2025255438A1 (en) | 2024-06-07 | 2025-12-11 | Revolution Medicines, Inc. | Methods of treating a ras protein-related disease or disorder |
| WO2025265060A1 (en) | 2024-06-21 | 2025-12-26 | Revolution Medicines, Inc. | Therapeutic compositions and methods for managing treatment-related effects |
| WO2026006747A1 (en) | 2024-06-28 | 2026-01-02 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2026015790A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Methods of treating a ras related disease or disorder |
| WO2026015796A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Methods of treating a ras related disease or disorder |
| WO2026015825A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Use of ras inhibitor for treating pancreatic cancer |
| WO2026015801A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Methods of treating a ras related disease or disorder |
| WO2026050446A1 (en) | 2024-08-29 | 2026-03-05 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2026072904A2 (en) | 2024-09-26 | 2026-04-02 | Revolution Medicines, Inc. | Compositions and methods for treating lung cancer |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008034008A2 (en) * | 2006-09-14 | 2008-03-20 | Deciphera Pharmaceuticals, Llc. | Kinase inhibitors useful for the treatment of proliferative diseases |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1447405A4 (en) * | 2001-10-17 | 2005-01-12 | Kirin Brewery | CHINOLIN OR CHINAZOLINE DERIVATIVES THAT PREVENT THE AUTOPHOSPHORYLATION OF RECEPTORS FOR THE FIBROBLAST GROWTH FACTOR |
| EP1566379A4 (en) * | 2002-10-29 | 2005-11-09 | Kirin Brewery | CHINOLINE DERIVATIVES AND CHINAZOLINE DERIVATIVES AS INHIBITORS OF FLT3 AUTOPHOSPHORYLATION AND THE MEDICAL COMPOSITIONS CONTAINING THEREOF |
| US20070054916A1 (en) | 2004-10-01 | 2007-03-08 | Amgen Inc. | Aryl nitrogen-containing bicyclic compounds and methods of use |
| US7897762B2 (en) | 2006-09-14 | 2011-03-01 | Deciphera Pharmaceuticals, Llc | Kinase inhibitors useful for the treatment of proliferative diseases |
| UY33221A (es) * | 2010-02-09 | 2011-09-30 | Univ California | MÉTODOS PARA TRATAR CÁNCER USANDO INHIBIDORES DE PI3K Y mTOR EN COMBINACIÓN CON INHIBIDORES DE AUTOFAGIA |
| AR090151A1 (es) * | 2012-03-07 | 2014-10-22 | Lilly Co Eli | Compuestos inhibidores de raf |
-
2013
- 2013-02-26 AR ARP130100576A patent/AR090151A1/es unknown
- 2013-02-27 TW TW102107122A patent/TW201348233A/zh unknown
- 2013-03-05 WO PCT/US2013/029098 patent/WO2013134252A1/en not_active Ceased
- 2013-03-05 CN CN201380012913.9A patent/CN104302646B/zh not_active Expired - Fee Related
- 2013-03-05 WO PCT/US2013/029084 patent/WO2013134243A1/en not_active Ceased
- 2013-03-05 EA EA201491456A patent/EA024824B1/ru not_active IP Right Cessation
- 2013-03-05 PT PT137120051T patent/PT2850082T/pt unknown
- 2013-03-05 NZ NZ627454A patent/NZ627454A/en not_active IP Right Cessation
- 2013-03-05 SG SG11201404969YA patent/SG11201404969YA/en unknown
- 2013-03-05 HK HK15103082.6A patent/HK1202541A1/xx unknown
- 2013-03-05 PE PE2014001381A patent/PE20142338A1/es not_active Application Discontinuation
- 2013-03-05 KR KR1020147024732A patent/KR20140129087A/ko not_active Abandoned
- 2013-03-05 MX MX2014010701A patent/MX2014010701A/es unknown
- 2013-03-05 US US13/785,575 patent/US8741911B2/en not_active Expired - Fee Related
- 2013-03-05 RS RS20160416A patent/RS54840B1/sr unknown
- 2013-03-05 IN IN1575MUN2014 patent/IN2014MN01575A/en unknown
- 2013-03-05 AU AU2013230146A patent/AU2013230146B2/en not_active Ceased
- 2013-03-05 HR HRP20160654TT patent/HRP20160654T1/hr unknown
- 2013-03-05 JP JP2014561029A patent/JP2015509536A/ja not_active Ceased
- 2013-03-05 HU HUE13712005A patent/HUE028095T2/en unknown
- 2013-03-05 US US14/383,799 patent/US9334267B2/en not_active Expired - Fee Related
- 2013-03-05 ME MEP-2016-124A patent/ME02423B/me unknown
- 2013-03-05 CA CA2863673A patent/CA2863673A1/en not_active Abandoned
- 2013-03-05 EP EP13712005.1A patent/EP2850082B1/en active Active
- 2013-03-05 MA MA37316A patent/MA37316B1/fr unknown
- 2013-03-05 AP AP2014007899A patent/AP2014007899A0/xx unknown
- 2013-03-05 LT LTEP13712005.1T patent/LT2850082T/lt unknown
- 2013-03-05 ES ES13712005.1T patent/ES2584387T3/es active Active
- 2013-03-05 DK DK13712005.1T patent/DK2850082T3/en active
- 2013-03-05 SI SI201330188A patent/SI2850082T1/sl unknown
- 2013-03-05 BR BR112014018528A patent/BR112014018528A8/pt not_active IP Right Cessation
- 2013-05-03 UA UAA201409109A patent/UA112340C2/uk unknown
-
2014
- 2014-07-24 CO CO14161404A patent/CO7010837A2/es unknown
- 2014-08-11 IL IL234052A patent/IL234052A/en not_active IP Right Cessation
- 2014-08-12 CR CR20140378A patent/CR20140378A/es unknown
- 2014-08-21 CL CL2014002220A patent/CL2014002220A1/es unknown
- 2014-09-03 TN TNP2014000375A patent/TN2014000375A1/fr unknown
- 2014-09-04 DO DO2014000200A patent/DOP2014000200A/es unknown
- 2014-09-05 EC ECIEPI201417584A patent/ECSP14017584A/es unknown
- 2014-09-05 PH PH12014501986A patent/PH12014501986A1/en unknown
-
2016
- 2016-07-22 CY CY20161100719T patent/CY1117846T1/el unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008034008A2 (en) * | 2006-09-14 | 2008-03-20 | Deciphera Pharmaceuticals, Llc. | Kinase inhibitors useful for the treatment of proliferative diseases |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2013230146B2 (en) | 2-amino, 6-phenyl substituted pyrido [2, 3 - d] pyrimidine derivatives useful as Raf kinase inhibitors | |
| CN107922425B (zh) | 制备parp抑制剂、结晶形式的方法及其用途 | |
| CN109689641B (zh) | 一种取代的2-氢-吡唑衍生物的晶型、盐型及其制备方法 | |
| WO2013134298A1 (en) | Raf inhibitor compounds | |
| KR20080002958A (ko) | 단백질 키나제 억제제로서 적합한 페닐아세트아미드 | |
| CN113454081A (zh) | 咪唑并吡啶基化合物及其用于治疗增生性疾病的用途 | |
| WO2020125759A1 (zh) | 作为wnt信号通路抑制剂的化合物及其医学应用 | |
| WO2020114388A1 (zh) | 取代的吡唑并[1,5-a]吡啶化合物及包含该化合物的组合物及其用途 | |
| WO2016112846A1 (zh) | 3-乙炔基吡唑并嘧啶衍生物及其制备方法和用途 | |
| WO2021023888A1 (en) | Isoquinoline derivatives as protein kinase inhibitors | |
| CN107793371B (zh) | 一类溴结构域识别蛋白抑制剂及其制备方法和用途 | |
| WO2023036252A1 (zh) | 吡咯并嘧啶类或吡咯并吡啶类衍生物及其医药用途 | |
| CN111303128B (zh) | 一种多环类化合物、其制备方法及应用 | |
| TWI546304B (zh) | Protein tyrosine kinase inhibitors and their use | |
| MX2014009524A (es) | Derivados de triazolopiridina como un inhibidor de quinasa tirosina. | |
| AU2013207082A1 (en) | Therapeutic use of imidazopyridine derivatives | |
| HK40040143A (en) | Process for preparing parp inhibitor, crystalline forms, and uses thereof | |
| JP2025526715A (ja) | ピリジノピリミジノン化合物の結晶、その酸塩、その酸塩の結晶及び使用 | |
| WO2023082044A1 (zh) | 5-醛基杂环酰胺类化合物及其应用 | |
| WO2025008526A1 (en) | Compounds containing a dialkylaryl moiety and their use | |
| WO2026061424A1 (zh) | 一种化合物、包含其的药物组合物及其用途 | |
| CN116102549A (zh) | 5-醛基杂环酰胺类化合物及其应用 | |
| HK40058867A (en) | Imidazopyridinyl compounds and use thereof for treatment of proliferative disorders |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FGA | Letters patent sealed or granted (standard patent) | ||
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |