RU2563193C2 - Комбинации ингибитора pi3k и ингибитора мек - Google Patents
Комбинации ингибитора pi3k и ингибитора мек Download PDFInfo
- Publication number
- RU2563193C2 RU2563193C2 RU2012118974/15A RU2012118974A RU2563193C2 RU 2563193 C2 RU2563193 C2 RU 2563193C2 RU 2012118974/15 A RU2012118974/15 A RU 2012118974/15A RU 2012118974 A RU2012118974 A RU 2012118974A RU 2563193 C2 RU2563193 C2 RU 2563193C2
- Authority
- RU
- Russia
- Prior art keywords
- gdc
- compound
- patient
- combination
- present
- Prior art date
Links
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 title description 57
- 229940124647 MEK inhibitor Drugs 0.000 title description 44
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 title description 10
- 239000012828 PI3K inhibitor Substances 0.000 title description 9
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 117
- 238000000034 method Methods 0.000 claims abstract description 66
- 238000011282 treatment Methods 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- 239000000203 mixture Substances 0.000 claims abstract description 19
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 18
- 241000124008 Mammalia Species 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 131
- 230000001394 metastastic effect Effects 0.000 claims description 45
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 45
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 3
- 102000038030 PI3Ks Human genes 0.000 abstract description 20
- 108091007960 PI3Ks Proteins 0.000 abstract description 20
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 abstract description 18
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 abstract description 14
- 239000003112 inhibitor Substances 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 6
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 239000013543 active substance Substances 0.000 abstract 1
- 230000002195 synergetic effect Effects 0.000 abstract 1
- BSMCAPRUBJMWDF-KRWDZBQOSA-N cobimetinib Chemical compound C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F BSMCAPRUBJMWDF-KRWDZBQOSA-N 0.000 description 199
- 229960002271 cobimetinib Drugs 0.000 description 197
- LHNIIDJUOCFXAP-UHFFFAOYSA-N pictrelisib Chemical compound C1CN(S(=O)(=O)C)CCN1CC1=CC2=NC(C=3C=4C=NNC=4C=CC=3)=NC(N3CCOCC3)=C2S1 LHNIIDJUOCFXAP-UHFFFAOYSA-N 0.000 description 128
- 239000003795 chemical substances by application Substances 0.000 description 31
- 101150040459 RAS gene Proteins 0.000 description 29
- 101150076031 RAS1 gene Proteins 0.000 description 28
- 102000016914 ras Proteins Human genes 0.000 description 28
- 230000037353 metabolic pathway Effects 0.000 description 26
- 239000002904 solvent Substances 0.000 description 25
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 23
- 201000011510 cancer Diseases 0.000 description 22
- -1 gentisinates Chemical class 0.000 description 16
- 230000035772 mutation Effects 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- 201000010099 disease Diseases 0.000 description 11
- 201000001441 melanoma Diseases 0.000 description 11
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 11
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 11
- 230000004044 response Effects 0.000 description 10
- 239000011435 rock Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 9
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 9
- 230000006872 improvement Effects 0.000 description 9
- 208000037843 metastatic solid tumor Diseases 0.000 description 9
- 230000004614 tumor growth Effects 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 230000007123 defense Effects 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 230000004913 activation Effects 0.000 description 7
- 239000010432 diamond Substances 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 239000012453 solvate Substances 0.000 description 7
- 239000002253 acid Substances 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 208000029742 colonic neoplasm Diseases 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 230000035945 sensitivity Effects 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 108091054455 MAP kinase family Proteins 0.000 description 5
- 210000001072 colon Anatomy 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 231100000590 oncogenic Toxicity 0.000 description 5
- 230000002246 oncogenic effect Effects 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 230000019491 signal transduction Effects 0.000 description 5
- 230000001629 suppression Effects 0.000 description 5
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- 239000012981 Hank's balanced salt solution Substances 0.000 description 4
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 4
- 108060006687 MAP kinase kinase kinase Proteins 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 206010033128 Ovarian cancer Diseases 0.000 description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 description 4
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 4
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000002207 metabolite Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 238000011269 treatment regimen Methods 0.000 description 4
- XUHRVZXFBWDCFB-QRTDKPMLSA-N (3R)-4-[[(3S,6S,9S,12R,15S,18R,21R,24R,27R,28R)-12-(3-amino-3-oxopropyl)-6-[(2S)-butan-2-yl]-3-(2-carboxyethyl)-18-(hydroxymethyl)-28-methyl-9,15,21,24-tetrakis(2-methylpropyl)-2,5,8,11,14,17,20,23,26-nonaoxo-1-oxa-4,7,10,13,16,19,22,25-octazacyclooctacos-27-yl]amino]-3-[[(2R)-2-[[(3S)-3-hydroxydecanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoic acid Chemical compound CCCCCCC[C@H](O)CC(=O)N[C@H](CC(C)C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H]1[C@@H](C)OC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CO)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC1=O)[C@@H](C)CC XUHRVZXFBWDCFB-QRTDKPMLSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102000001301 EGF receptor Human genes 0.000 description 3
- 108060006698 EGF receptor Proteins 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 102100030708 GTPase KRas Human genes 0.000 description 3
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 102000043136 MAP kinase family Human genes 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699660 Mus musculus Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 108010091528 Proto-Oncogene Proteins B-raf Proteins 0.000 description 3
- 208000015634 Rectal Neoplasms Diseases 0.000 description 3
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 3
- 102100024547 Tensin-1 Human genes 0.000 description 3
- 108010088950 Tensins Proteins 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 108010082117 matrigel Proteins 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 238000011580 nude mouse model Methods 0.000 description 3
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 description 3
- 206010038038 rectal cancer Diseases 0.000 description 3
- 201000001275 rectum cancer Diseases 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 102200006538 rs121913530 Human genes 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 238000010176 18-FDG-positron emission tomography Methods 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- ZCXUVYAZINUVJD-AHXZWLDOSA-N 2-deoxy-2-((18)F)fluoro-alpha-D-glucose Chemical compound OC[C@H]1O[C@H](O)[C@H]([18F])[C@@H](O)[C@@H]1O ZCXUVYAZINUVJD-AHXZWLDOSA-N 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 206010052747 Adenocarcinoma pancreas Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OCUCCJIRFHNWBP-IYEMJOQQSA-L Copper gluconate Chemical class [Cu+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O OCUCCJIRFHNWBP-IYEMJOQQSA-L 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 102100039788 GTPase NRas Human genes 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- 206010064571 Gene mutation Diseases 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 2
- 101001050288 Homo sapiens Transcription factor Jun Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 206010069755 K-ras gene mutation Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 description 2
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 206010033701 Papillary thyroid cancer Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 102000018471 Proto-Oncogene Proteins B-raf Human genes 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 206010038019 Rectal adenocarcinoma Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102100023132 Transcription factor Jun Human genes 0.000 description 2
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 description 2
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 150000001860 citric acid derivatives Chemical class 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 201000010897 colon adenocarcinoma Diseases 0.000 description 2
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 2
- 238000007257 deesterification reaction Methods 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108010077182 raf Kinases Proteins 0.000 description 2
- 102000009929 raf Kinases Human genes 0.000 description 2
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 2
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 2
- 201000001281 rectum adenocarcinoma Diseases 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- YOVVNQKCSKSHKT-HNNXBMFYSA-N (2s)-1-[4-[[2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl]piperazin-1-yl]-2-hydroxypropan-1-one Chemical compound C1CN(C(=O)[C@@H](O)C)CCN1CC1=C(C)C2=NC(C=3C=NC(N)=NC=3)=NC(N3CCOCC3)=C2S1 YOVVNQKCSKSHKT-HNNXBMFYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 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 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical class C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UPMLOUAZCHDJJD-UHFFFAOYSA-N 4,4'-Diphenylmethane Diisocyanate Chemical compound C1=CC(N=C=O)=CC=C1CC1=CC=C(N=C=O)C=C1 UPMLOUAZCHDJJD-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010069754 Acquired gene mutation Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- DKHRKXVROBCSCB-UHFFFAOYSA-N CC(C)(C)CNCC(C1)(CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)ccc1F)=O)O Chemical compound CC(C)(C)CNCC(C1)(CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)ccc1F)=O)O DKHRKXVROBCSCB-UHFFFAOYSA-N 0.000 description 1
- IAMJQTYVPDHYAO-UHFFFAOYSA-O CC(C)(C)OC(NCCCNCC(C1)(CN1C(c(ccc(F)c1F)c1Nc(ccc(I)c1)c1F)=O)[OH2+])=O Chemical compound CC(C)(C)OC(NCCCNCC(C1)(CN1C(c(ccc(F)c1F)c1Nc(ccc(I)c1)c1F)=O)[OH2+])=O IAMJQTYVPDHYAO-UHFFFAOYSA-O 0.000 description 1
- FVQHSEGKGZPNJC-UHFFFAOYSA-N CC(C)NCCC(C1)(CN1C(c(c(Nc(c(F)c1)ccc1I)c1F)ccc1F)=O)O Chemical compound CC(C)NCCC(C1)(CN1C(c(c(Nc(c(F)c1)ccc1I)c1F)ccc1F)=O)O FVQHSEGKGZPNJC-UHFFFAOYSA-N 0.000 description 1
- 0 CCC(C)(CCCCC1)[C@@]1(C)C(C1)(C*1C(c(cc1)c(*c2ccc(*)cc2N)c(N)c1N)=O)O Chemical compound CCC(C)(CCCCC1)[C@@]1(C)C(C1)(C*1C(c(cc1)c(*c2ccc(*)cc2N)c(N)c1N)=O)O 0.000 description 1
- LRPCYOVVRUEVMG-UHFFFAOYSA-N CCCCC[F]c(ccc(C(N(C1)CC1(CNC(Cc1ccccc1)CO)O)=O)c1Nc(ccc(I)c2)c2F)c1F Chemical compound CCCCC[F]c(ccc(C(N(C1)CC1(CNC(Cc1ccccc1)CO)O)=O)c1Nc(ccc(I)c2)c2F)c1F LRPCYOVVRUEVMG-UHFFFAOYSA-N 0.000 description 1
- SCUAYKVDYLZMPF-UHFFFAOYSA-N CCN(CC)CC(NC(C1)CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)ccc1F)=O)=O Chemical compound CCN(CC)CC(NC(C1)CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)ccc1F)=O)=O SCUAYKVDYLZMPF-UHFFFAOYSA-N 0.000 description 1
- GPQHMKDPNKOZDY-UHFFFAOYSA-N CCN(CC)CCNC(C(C1)CN1C(c(ccc(F)c1F)c1Nc(ccc(C)c1)c1F)=O)=O Chemical compound CCN(CC)CCNC(C(C1)CN1C(c(ccc(F)c1F)c1Nc(ccc(C)c1)c1F)=O)=O GPQHMKDPNKOZDY-UHFFFAOYSA-N 0.000 description 1
- OYMDCRHCYRWTCR-HNNXBMFYSA-N CC[C@@H](C(C1)(CN1C(c(ccc(F)c1F)c1Nc(ccc(I)c1)c1F)=O)O)N Chemical compound CC[C@@H](C(C1)(CN1C(c(ccc(F)c1F)c1Nc(ccc(I)c1)c1F)=O)O)N OYMDCRHCYRWTCR-HNNXBMFYSA-N 0.000 description 1
- XOFLMGUKOUNOIQ-UHFFFAOYSA-N CN(C)CC(C1)CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)ccc1F)=O Chemical compound CN(C)CC(C1)CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)ccc1F)=O XOFLMGUKOUNOIQ-UHFFFAOYSA-N 0.000 description 1
- QBOXADHIDZVGOX-UHFFFAOYSA-O CN(C)CCCCNCC(C1)(CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)ccc1F)=O)[OH2+] Chemical compound CN(C)CCCCNCC(C1)(CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)ccc1F)=O)[OH2+] QBOXADHIDZVGOX-UHFFFAOYSA-O 0.000 description 1
- DXMKEEXDTZCJHQ-UHFFFAOYSA-N CN(CCC1)C1C(C1)(CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)ccc1F)=O)O Chemical compound CN(CCC1)C1C(C1)(CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)ccc1F)=O)O DXMKEEXDTZCJHQ-UHFFFAOYSA-N 0.000 description 1
- MVFQTZRVVGQVKX-UHFFFAOYSA-N CNCC(NC(C1)CN1C(c(c(Nc(c(F)c1)ccc1I)c1F)ccc1F)=O)=O Chemical compound CNCC(NC(C1)CN1C(c(c(Nc(c(F)c1)ccc1I)c1F)ccc1F)=O)=O MVFQTZRVVGQVKX-UHFFFAOYSA-N 0.000 description 1
- KDASDFXDUSQTEF-LBPRGKRZSA-N C[C@@H](C(C1)(CN1C(c(c(Nc(ccc(I)c1)c1F)c1)cc2c1nn[n]2C)=O)O)N(C)C Chemical compound C[C@@H](C(C1)(CN1C(c(c(Nc(ccc(I)c1)c1F)c1)cc2c1nn[n]2C)=O)O)N(C)C KDASDFXDUSQTEF-LBPRGKRZSA-N 0.000 description 1
- XLZVNDRYPILHRZ-JTQLQIEISA-N C[C@@H](C(C1)(CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)c[n]2c1ncc2)=O)O)N Chemical compound C[C@@H](C(C1)(CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)c[n]2c1ncc2)=O)O)N XLZVNDRYPILHRZ-JTQLQIEISA-N 0.000 description 1
- WSGMIYGGTLNFFO-UHFFFAOYSA-N C[n]1c2ccccc2nc1C(C1)(CN1C(C(C(Nc(ccc(Br)c1)c1F)=C1)=CN(C)C1=O)=O)O Chemical compound C[n]1c2ccccc2nc1C(C1)(CN1C(C(C(Nc(ccc(Br)c1)c1F)=C1)=CN(C)C1=O)=O)O WSGMIYGGTLNFFO-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- ZVWPVGKCCLALGU-UHFFFAOYSA-N Cc1nnc(CNCC(C2)(CN2C(c(ccc(F)c2F)c2Nc(ccc(I)c2)c2F)=O)O)[o]1 Chemical compound Cc1nnc(CNCC(C2)(CN2C(c(ccc(F)c2F)c2Nc(ccc(I)c2)c2F)=O)O)[o]1 ZVWPVGKCCLALGU-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000208377 Corynocarpus laevigatus Species 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-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
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 101710113436 GTPase KRas Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- HSRJKNPTNIJEKV-UHFFFAOYSA-N Guaifenesin Chemical compound COC1=CC=CC=C1OCC(O)CO HSRJKNPTNIJEKV-UHFFFAOYSA-N 0.000 description 1
- 101500025419 Homo sapiens Epidermal growth factor Proteins 0.000 description 1
- 101000950687 Homo sapiens Mitogen-activated protein kinase 7 Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 238000004566 IR spectroscopy Methods 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
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 description 1
- 101710184277 Insulin-like growth factor 1 receptor Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 150000000994 L-ascorbates Chemical class 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241000404172 Minois dryas Species 0.000 description 1
- 102100023482 Mitogen-activated protein kinase 14 Human genes 0.000 description 1
- 102100037805 Mitogen-activated protein kinase 7 Human genes 0.000 description 1
- 101100381978 Mus musculus Braf gene Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- GALVRNPRTPCQSJ-UHFFFAOYSA-N N=C(NCC(C1)(CN1C(c(c(Nc(c(F)c1)ccc1I)c1F)ccc1F)=O)O)N[N+]([O-])=O Chemical compound N=C(NCC(C1)(CN1C(c(c(Nc(c(F)c1)ccc1I)c1F)ccc1F)=O)O)N[N+]([O-])=O GALVRNPRTPCQSJ-UHFFFAOYSA-N 0.000 description 1
- WCTVCFJXXOULOX-UHFFFAOYSA-O NC(C(C1)(CN1C(c(ccc(F)c1F)c1Nc(ccc(I)c1)c1F)=O)[OH2+])c1ccccc1 Chemical compound NC(C(C1)(CN1C(c(ccc(F)c1F)c1Nc(ccc(I)c1)c1F)=O)[OH2+])c1ccccc1 WCTVCFJXXOULOX-UHFFFAOYSA-O 0.000 description 1
- 101150073096 NRAS gene Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000006057 Non-nutritive feed additive Substances 0.000 description 1
- RYCDHSOZXZRDCJ-HNNXBMFYSA-N OC(C1)(CN1C(C(C(Nc(ccc(I)c1)c1F)=N1)=CNC1=O)=O)[C@H]1NCCCC1 Chemical compound OC(C1)(CN1C(C(C(Nc(ccc(I)c1)c1F)=N1)=CNC1=O)=O)[C@H]1NCCCC1 RYCDHSOZXZRDCJ-HNNXBMFYSA-N 0.000 description 1
- ARCRFSOHPIEFDF-KRWDZBQOSA-N OC(C1)(CN1C(c(c(Nc(ccc(Br)c1)c1F)c1F)c[n]2c1ncc2)=O)[C@H]1NCCCC1 Chemical compound OC(C1)(CN1C(c(c(Nc(ccc(Br)c1)c1F)c1F)c[n]2c1ncc2)=O)[C@H]1NCCCC1 ARCRFSOHPIEFDF-KRWDZBQOSA-N 0.000 description 1
- ZBUWGJXWWFFEIM-SFHVURJKSA-N OC(C1)(CN1C(c1cccc(F)c1Nc(ccc(I)c1)c1F)=O)[C@H]1NCCCC1 Chemical compound OC(C1)(CN1C(c1cccc(F)c1Nc(ccc(I)c1)c1F)=O)[C@H]1NCCCC1 ZBUWGJXWWFFEIM-SFHVURJKSA-N 0.000 description 1
- YATWQQYUFRSTKN-UHFFFAOYSA-N OC(CNC1CC1)(C1)CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)ccc1F)=O Chemical compound OC(CNC1CC1)(C1)CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)ccc1F)=O YATWQQYUFRSTKN-UHFFFAOYSA-N 0.000 description 1
- ZUFGQEYMNJEORL-UHFFFAOYSA-N OC(CNCC(F)(F)F)(C1)CN1C(c(ccc(F)c1F)c1Nc(ccc(I)c1)c1F)=O Chemical compound OC(CNCC(F)(F)F)(C1)CN1C(c(ccc(F)c1F)c1Nc(ccc(I)c1)c1F)=O ZUFGQEYMNJEORL-UHFFFAOYSA-N 0.000 description 1
- KBQRJDURDIWHKF-UHFFFAOYSA-N OC(CNCc(cc1)ccc1O)(C1)CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)ccc1F)=O Chemical compound OC(CNCc(cc1)ccc1O)(C1)CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)ccc1F)=O KBQRJDURDIWHKF-UHFFFAOYSA-N 0.000 description 1
- UXWZVHTVUNKYJT-UHFFFAOYSA-N OCCCCNCC(C1)(CN1C(c(ccc(F)c1F)c1Nc(ccc(I)c1)c1F)=O)O Chemical compound OCCCCNCC(C1)(CN1C(c(ccc(F)c1F)c1Nc(ccc(I)c1)c1F)=O)O UXWZVHTVUNKYJT-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- FLJPTCVWWWBETI-UHFFFAOYSA-N [O-]C(CNc1cc(F)ccc1)(C1)CN1C(c(ccc(F)c1F)c1Nc(ccc(I)c1)c1F)=O Chemical compound [O-]C(CNc1cc(F)ccc1)(C1)CN1C(c(ccc(F)c1F)c1Nc(ccc(I)c1)c1F)=O FLJPTCVWWWBETI-UHFFFAOYSA-N 0.000 description 1
- HYDLHIUWUUDUOE-UHFFFAOYSA-O [OH2+]C(CNc1ccccc1)(C1)CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)ccc1F)=O Chemical compound [OH2+]C(CNc1ccccc1)(C1)CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)ccc1F)=O HYDLHIUWUUDUOE-UHFFFAOYSA-O 0.000 description 1
- UCBHQAVTBYMWDV-UHFFFAOYSA-O [OH2+]C(COc1ccccc1)(C1)CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)ccc1F)=O Chemical compound [OH2+]C(COc1ccccc1)(C1)CN1C(c(c(Nc(ccc(I)c1)c1F)c1F)ccc1F)=O UCBHQAVTBYMWDV-UHFFFAOYSA-O 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 229910000287 alkaline earth metal oxide Inorganic materials 0.000 description 1
- 229940061720 alpha hydroxy acid Drugs 0.000 description 1
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000012512 bulk drug substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- JJWKPURADFRFRB-UHFFFAOYSA-N carbonyl sulfide Chemical compound O=C=S JJWKPURADFRFRB-UHFFFAOYSA-N 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 235000021474 generally recognized As safe (food) Nutrition 0.000 description 1
- 235000021473 generally recognized as safe (food ingredients) Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 229940116978 human epidermal growth factor Drugs 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical class OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- GVUGOAYIVIDWIO-UFWWTJHBSA-N nepidermin Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CS)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C(C)C)C(C)C)C1=CC=C(O)C=C1 GVUGOAYIVIDWIO-UFWWTJHBSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 201000004228 ovarian endometrial cancer Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 208000017058 pharyngeal squamous cell carcinoma Diseases 0.000 description 1
- 239000002935 phosphatidylinositol 3 kinase inhibitor Substances 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000037439 somatic mutation Effects 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 231100000747 viability assay Toxicity 0.000 description 1
- 238000003026 viability measurement method Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further 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
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US25085209P | 2009-10-12 | 2009-10-12 | |
| US61/250,852 | 2009-10-12 | ||
| PCT/EP2010/065149 WO2011054620A1 (en) | 2009-10-12 | 2010-10-11 | Combinations of a pi3k inhibitor and a mek inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| RU2012118974A RU2012118974A (ru) | 2013-11-20 |
| RU2563193C2 true RU2563193C2 (ru) | 2015-09-20 |
Family
ID=43072663
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2012118974/15A RU2563193C2 (ru) | 2009-10-12 | 2010-10-11 | Комбинации ингибитора pi3k и ингибитора мек |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US20110086837A1 (https=) |
| EP (1) | EP2488178B1 (https=) |
| JP (2) | JP2013507415A (https=) |
| KR (1) | KR101489045B1 (https=) |
| CN (1) | CN102740851B (https=) |
| AR (1) | AR078588A1 (https=) |
| AU (1) | AU2010314287A1 (https=) |
| BR (1) | BR112012008483A2 (https=) |
| CA (1) | CA2776944A1 (https=) |
| CL (1) | CL2012000913A1 (https=) |
| CO (1) | CO6531463A2 (https=) |
| CR (1) | CR20120173A (https=) |
| EC (1) | ECSP12011865A (https=) |
| ES (1) | ES2609767T3 (https=) |
| IL (1) | IL219105A0 (https=) |
| MA (1) | MA33974B1 (https=) |
| MX (1) | MX345155B (https=) |
| NZ (1) | NZ599939A (https=) |
| PE (1) | PE20121816A1 (https=) |
| PH (1) | PH12012500709A1 (https=) |
| RU (1) | RU2563193C2 (https=) |
| TW (1) | TWI428336B (https=) |
| WO (1) | WO2011054620A1 (https=) |
| ZA (1) | ZA201202618B (https=) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110105521A1 (en) | 2008-07-11 | 2011-05-05 | Novartis Ag | Combination of (a) a phosphoinositide 3-kinase inhibitor and (b) a modulator of ras/raf/mek pathway |
| EA024252B1 (ru) | 2009-01-08 | 2016-08-31 | Кьюрис, Инк. | Ингибиторы фосфоинозитид-3-киназ с цинксвязывающей группой |
| PH12012501361A1 (en) | 2009-12-31 | 2012-10-22 | Centro Nac De Investigaciones Oncologicas Cnio | Tricyclic compounds for use as kinase inhibitors |
| WO2012098387A1 (en) | 2011-01-18 | 2012-07-26 | Centro Nacional De Investigaciones Oncológicas (Cnio) | 6, 7-ring-fused triazolo [4, 3 - b] pyridazine derivatives as pim inhibitors |
| WO2012135571A1 (en) | 2011-04-01 | 2012-10-04 | Curis, Inc. | Phosphoinositide 3-kinase inhibitor with a zinc binding moiety |
| MX368257B (es) | 2011-08-01 | 2019-09-26 | Genentech Inc | Antagonistas de unión al eje pd-1e inhibidores de mek y sus usos en el tratamiento de cáncer. |
| KR20140072028A (ko) * | 2011-08-31 | 2014-06-12 | 노파르티스 아게 | Pi3k- 및 mek-억제제의 상승작용적 조합물 |
| CA2849331A1 (en) | 2011-10-13 | 2013-04-18 | Genentech, Inc. | Treatment of pharmacological-induced hypochlorhydria |
| MX2014004991A (es) * | 2011-10-28 | 2014-05-22 | Genentech Inc | Combinaciones terapeuticas y metodos para tratar el melanoma. |
| WO2013082511A1 (en) | 2011-12-02 | 2013-06-06 | Genentech, Inc. | Methods for overcoming tumor resistance to vegf antagonists |
| AU2013243429A1 (en) * | 2012-04-06 | 2014-10-23 | Merck Patent Gmbh | Methods for treating cancer using PI3K inhibitor and MEK inhibitor |
| WO2013157648A1 (ja) * | 2012-04-19 | 2013-10-24 | 国立大学法人九州大学 | 医薬組成物 |
| BR112014028376A2 (pt) | 2012-06-08 | 2018-04-24 | Hoffmann La Roche | métodos para o tratamento de um distúrbio hiperproliferativo, para a determinação dos compostos, para monitorar, para optimizar a eficácia terapêutica e de identificação de um biomarcador; formulação farmacêutica; utilização de uma combinação terapêutica e de gdc-0032, artigo de manufatura, produto e invenção |
| CA2879670A1 (en) | 2012-08-02 | 2014-02-06 | Genentech, Inc. | Anti-etbr antibodies and immunoconjugates |
| JP2015528818A (ja) | 2012-08-02 | 2015-10-01 | ジェネンテック， インコーポレイテッド | 抗ｅｔｂｒ抗体およびイムノコンジュゲート |
| KR20190057421A (ko) | 2012-08-17 | 2019-05-28 | 에프. 호프만-라 로슈 아게 | 코비메티닙 및 베무라피닙을 투여함을 포함하는 흑색종의 조합 치료법 |
| MX2015010854A (es) * | 2013-03-14 | 2016-07-20 | Genentech Inc | Combinaciones de un compuesto inhibidor de mek con un compuesto inhibidor de her3/egfr y metodos de uso. |
| US9532987B2 (en) | 2013-09-05 | 2017-01-03 | Genentech, Inc. | Use of a combination of a MEK inhibitor and an ERK inhibitor for treatment of hyperproliferative diseases |
| WO2015120289A1 (en) | 2014-02-07 | 2015-08-13 | Verastem, Inc. | Methods and compositions for treating abnormal cell growth |
| EP3563870A1 (en) | 2014-07-15 | 2019-11-06 | F. Hoffmann-La Roche AG | Methods of treating cancer using pd-1 axis binding antagonists and mek inhibitors |
| CN113620978A (zh) * | 2014-09-11 | 2021-11-09 | 加利福尼亚大学董事会 | mTORC1抑制剂 |
| CN113164466B (zh) | 2018-09-11 | 2025-07-08 | 柯瑞斯公司 | 使用具有锌结合部分的磷酸肌醇3-激酶抑制剂的联合治疗 |
| CN110420330B (zh) * | 2019-07-19 | 2020-05-29 | 南京医科大学 | 一种pi3k与mth1靶向药组合物的制药用途 |
| JP2022547358A (ja) | 2019-09-13 | 2022-11-14 | ジ インスティテュート オブ キャンサー リサーチ：ロイヤル キャンサー ホスピタル | 治療組成物、組み合わせ、及び使用方法 |
| US11873296B2 (en) | 2022-06-07 | 2024-01-16 | Verastem, Inc. | Solid forms of a dual RAF/MEK inhibitor |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006046031A1 (en) * | 2004-10-25 | 2006-05-04 | Piramed Limited | Pharmaceutical compounds |
| WO2007129161A2 (en) * | 2006-04-26 | 2007-11-15 | F. Hoffmann-La Roche Ag | Thieno [3, 2-d] pyrimidine derivative useful as pi3k inhibitor |
| US20090156576A1 (en) * | 2005-10-07 | 2009-06-18 | Exelixis Inc. | Azetidines as MEK Inhibitors for the Treatment of Proliferative Diseases |
Family Cites Families (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1470356A1 (de) * | 1964-01-15 | 1970-04-30 | Thomae Gmbh Dr K | Neue Thieno[3,2-d]pyrimidine und Verfahren zu ihrer Herstellung |
| BE754606A (fr) * | 1969-08-08 | 1971-02-08 | Thomae Gmbh Dr K | Nouvelles 2-aminoalcoylamino-thieno(3,2-d)pyrimidines et leurs procedesde fabrication |
| BE759493A (fr) * | 1969-11-26 | 1971-05-25 | Thomae Gmbh Dr K | Nouvelles 2-(5-nitro-2-furyl)-thieno(3,2-d) pyrimidines et procedes pour les fabriquer |
| US3763156A (en) * | 1970-01-28 | 1973-10-02 | Boehringer Sohn Ingelheim | 2-heterocyclic amino-4-morpholinothieno(3,2-d)pyrimidines |
| CH592668A5 (https=) * | 1973-10-02 | 1977-10-31 | Delalande Sa | |
| GB1570494A (en) * | 1975-11-28 | 1980-07-02 | Ici Ltd | Thienopyrimidine derivatives and their use as pesticides |
| US4510139A (en) * | 1984-01-06 | 1985-04-09 | Sterling Drug Inc. | Substituted aminobenzamides and their use as agents which inhibit lipoxygenase activity |
| AU685933B2 (en) * | 1994-04-01 | 1998-01-29 | Shionogi & Co., Ltd. | Oxime derivative and bactericide containing the same as active ingredient |
| US6974878B2 (en) * | 2001-03-21 | 2005-12-13 | Symyx Technologies, Inc. | Catalyst ligands, catalytic metal complexes and processes using same |
| US6608053B2 (en) * | 2000-04-27 | 2003-08-19 | Yamanouchi Pharmaceutical Co., Ltd. | Fused heteroaryl derivatives |
| US7498304B2 (en) * | 2000-06-16 | 2009-03-03 | Curis, Inc. | Angiogenesis-modulating compositions and uses |
| JP3811775B2 (ja) * | 2000-07-19 | 2006-08-23 | ワーナー−ランバート カンパニー リミティド ライアビリティー カンパニー | ４−ヨードフェニルアミノベンズヒドロキサム酸の酸素化エステル |
| US7235537B2 (en) * | 2002-03-13 | 2007-06-26 | Array Biopharma, Inc. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
| US7521447B2 (en) * | 2003-03-03 | 2009-04-21 | Array Biopharma Inc. | P38 inhibitors and methods of use thereof |
| US20050049276A1 (en) * | 2003-07-23 | 2005-03-03 | Warner-Lambert Company, Llc | Imidazopyridines and triazolopyridines |
| US7144907B2 (en) * | 2003-09-03 | 2006-12-05 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
| US7538120B2 (en) * | 2003-09-03 | 2009-05-26 | Array Biopharma Inc. | Method of treating inflammatory diseases |
| TW200520745A (en) * | 2003-09-19 | 2005-07-01 | Chugai Pharmaceutical Co Ltd | Novel 4-phenylamino-benzaldoxime derivatives and uses thereof as mitogen-activated protein kinase kinase (MEK) inhibitors |
| US7517994B2 (en) * | 2003-11-19 | 2009-04-14 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
| CN101528231A (zh) * | 2006-08-16 | 2009-09-09 | 埃克塞利希斯股份有限公司 | 在癌症的治疗中使用pi3k和mek调控剂 |
| MX2009005950A (es) * | 2006-12-07 | 2009-10-12 | Genentech Inc | Compuestos inhibidores de fosfoinositido 3-quinasas y metodos de uso. |
| EP2205242B1 (en) * | 2007-09-12 | 2015-04-15 | Genentech, Inc. | Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents, and methods of use |
| RU2013148817A (ru) * | 2011-04-01 | 2015-05-10 | Дженентек, Инк. | Комбинации соединений-ингибиторов акт и мек и способы их применения |
-
2010
- 2010-10-11 CA CA2776944A patent/CA2776944A1/en not_active Abandoned
- 2010-10-11 MX MX2012004286A patent/MX345155B/es active IP Right Grant
- 2010-10-11 PE PE2012000470A patent/PE20121816A1/es not_active Application Discontinuation
- 2010-10-11 KR KR1020127012069A patent/KR101489045B1/ko not_active Expired - Fee Related
- 2010-10-11 ES ES10768448.2T patent/ES2609767T3/es active Active
- 2010-10-11 RU RU2012118974/15A patent/RU2563193C2/ru not_active IP Right Cessation
- 2010-10-11 WO PCT/EP2010/065149 patent/WO2011054620A1/en not_active Ceased
- 2010-10-11 US US12/902,062 patent/US20110086837A1/en not_active Abandoned
- 2010-10-11 AU AU2010314287A patent/AU2010314287A1/en not_active Abandoned
- 2010-10-11 MA MA34821A patent/MA33974B1/fr unknown
- 2010-10-11 JP JP2012533589A patent/JP2013507415A/ja not_active Ceased
- 2010-10-11 EP EP10768448.2A patent/EP2488178B1/en not_active Not-in-force
- 2010-10-11 TW TW099134615A patent/TWI428336B/zh not_active IP Right Cessation
- 2010-10-11 PH PH1/2012/500709A patent/PH12012500709A1/en unknown
- 2010-10-11 NZ NZ599939A patent/NZ599939A/en not_active IP Right Cessation
- 2010-10-11 BR BR112012008483A patent/BR112012008483A2/pt not_active IP Right Cessation
- 2010-10-11 CN CN2010800563069A patent/CN102740851B/zh not_active Expired - Fee Related
- 2010-10-12 AR ARP100103706A patent/AR078588A1/es not_active Application Discontinuation
-
2012
- 2012-04-05 IL IL219105A patent/IL219105A0/en unknown
- 2012-04-10 CR CR20120173A patent/CR20120173A/es unknown
- 2012-04-11 CL CL2012000913A patent/CL2012000913A1/es unknown
- 2012-04-11 ZA ZA2012/02618A patent/ZA201202618B/en unknown
- 2012-04-20 CO CO12065784A patent/CO6531463A2/es not_active Application Discontinuation
- 2012-05-03 EC ECSP12011865 patent/ECSP12011865A/es unknown
-
2014
- 2014-10-01 JP JP2014202819A patent/JP5745678B2/ja not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006046031A1 (en) * | 2004-10-25 | 2006-05-04 | Piramed Limited | Pharmaceutical compounds |
| US20090156576A1 (en) * | 2005-10-07 | 2009-06-18 | Exelixis Inc. | Azetidines as MEK Inhibitors for the Treatment of Proliferative Diseases |
| WO2007129161A2 (en) * | 2006-04-26 | 2007-11-15 | F. Hoffmann-La Roche Ag | Thieno [3, 2-d] pyrimidine derivative useful as pi3k inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| Харкевич Д.А. Фармакология: Учебник. " 9-е изд., доп. и испр. " М.: ГЭОТАР-Медиа, 2006. " 736 с. Olga K. Mirzoeva et al / Basal Subtype and (MAPK)/ERK Kinase (MEK)-Phosphoinositide 3-Kinase Feedback Signaling Determine Susceptibility of Breast Cancer Cells to MEK Inhibition / Cancer Res / January 2009, Vol.69, N2, pages 565-572 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JP5745678B2 (ja) | 2015-07-08 |
| EP2488178B1 (en) | 2016-11-16 |
| CA2776944A1 (en) | 2011-05-12 |
| PE20121816A1 (es) | 2013-01-02 |
| NZ599939A (en) | 2014-02-28 |
| ZA201202618B (en) | 2014-10-29 |
| KR101489045B1 (ko) | 2015-02-02 |
| AR078588A1 (es) | 2011-11-16 |
| JP2015038110A (ja) | 2015-02-26 |
| US20110086837A1 (en) | 2011-04-14 |
| HK1175125A1 (en) | 2013-06-28 |
| MA33974B1 (fr) | 2013-02-01 |
| BR112012008483A2 (pt) | 2019-09-24 |
| CN102740851A (zh) | 2012-10-17 |
| AU2010314287A2 (en) | 2012-07-12 |
| CN102740851B (zh) | 2013-12-18 |
| TW201118082A (en) | 2011-06-01 |
| CR20120173A (es) | 2012-07-04 |
| PH12012500709A1 (en) | 2012-10-29 |
| ECSP12011865A (es) | 2012-06-29 |
| KR20120064132A (ko) | 2012-06-18 |
| EP2488178A1 (en) | 2012-08-22 |
| MX2012004286A (es) | 2012-05-22 |
| CL2012000913A1 (es) | 2012-09-14 |
| ES2609767T3 (es) | 2017-04-24 |
| CO6531463A2 (es) | 2012-09-28 |
| WO2011054620A1 (en) | 2011-05-12 |
| TWI428336B (zh) | 2014-03-01 |
| IL219105A0 (en) | 2012-06-28 |
| JP2013507415A (ja) | 2013-03-04 |
| AU2010314287A1 (en) | 2012-05-03 |
| RU2012118974A (ru) | 2013-11-20 |
| MX345155B (es) | 2017-01-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2563193C2 (ru) | Комбинации ингибитора pi3k и ингибитора мек | |
| Zhao et al. | The clinical development of MEK inhibitors | |
| JP2024526145A (ja) | Ｋｒａｓ ｇ１２ｃ阻害剤を含む組合せ医薬及び癌の治療のためのその使用 | |
| EP2205242B1 (en) | Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents, and methods of use | |
| AU2014233805B2 (en) | Combination therapy comprising a B-Raf inhibitor and a second inhibitor | |
| CN113840606A (zh) | 给药kras抑制剂治疗癌症 | |
| JP6855243B2 (ja) | 癌治療のためのアピリモド（ａｐｉｌｉｍｏｄ）組成物 | |
| RU2739992C2 (ru) | Композиции апилимода и способы их применения в лечении колоректального рака | |
| JP2020079243A (ja) | ＰＩ３Ｋインヒビターとｃ−Ｍｅｔインヒビターの組み合わせ | |
| JP2016529285A (ja) | 細胞増殖性疾患を治療するためのａｌｋ阻害剤とｃｄｋ阻害剤との組合せ | |
| CN115776889A (zh) | 用于治疗非小细胞肺癌的egfr tki | |
| EP4554581A1 (en) | Combination therapy comprising gspt1-directed molecular glue degraders and pi3k/akt/mtor pathway inhibitors | |
| KR20250121542A (ko) | 진행성 고형 종양의 치료 방법 | |
| JP2025530296A (ja) | 転移性癌を治療するためのｐｌｋ１阻害剤と抗血管新生剤の併用 | |
| HK1175125B (en) | Combinations of a pi3k inhibitor and a mek inhibitor | |
| WO2014031856A1 (en) | Combination therapy using pi3 kinase and braf inhibitors | |
| CN117043159A (zh) | Kras突变型癌症的治疗 | |
| HK40087830A (zh) | 用於癌症治疗的贝伐非尼 | |
| HK40121691A (zh) | 治疗cdk4/6抑制剂耐药性癌症的方法 | |
| CA3255718A1 (en) | Polytherapy involving GDC-6036 and GDC-0077 for cancer treatment | |
| HK1145287B (en) | Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents, and methods of use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | The patent is invalid due to non-payment of fees |
Effective date: 20171012 |