JP2013509444A - がんの治療方法及び治療用組成物 - Google Patents

Info

Publication number

JP2013509444A

JP2013509444A JP2012537178A JP2012537178A JP2013509444A JP 2013509444 A JP2013509444 A JP 2013509444A JP 2012537178 A JP2012537178 A JP 2012537178A JP 2012537178 A JP2012537178 A JP 2012537178A JP 2013509444 A JP2013509444 A JP 2013509444A

Authority

JP

Japan

Prior art keywords

compound

cancer

abl

cells

subject

Prior art date

2009-10-30

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.)

Pending

Links

• Espacenet
• Global Dossier
• Discuss

• 206010028980 Neoplasm Diseases 0.000 title claims abstract description 214
• 238000011282 treatment Methods 0.000 title claims abstract description 101
• 201000011510 cancer Diseases 0.000 title claims abstract description 82
• 238000000034 method Methods 0.000 title claims abstract description 77
• 239000000203 mixture Substances 0.000 title description 34
• 230000001225 therapeutic effect Effects 0.000 title description 9
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 36
• -1 imidazo [1,2-b] pyridazin-3-ylethynyl Chemical group 0.000 claims abstract description 31
• 229940125904 compound 1 Drugs 0.000 claims description 522
• WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 claims description 162
• 150000003839 salts Chemical class 0.000 claims description 139
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 79
• 201000010099 disease Diseases 0.000 claims description 76
• 229940124302 mTOR inhibitor Drugs 0.000 claims description 59
• 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 claims description 59
• 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 56
• 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 56
• 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 55
• 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 51
• ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 claims description 48
• 239000002067 L01XE06 - Dasatinib Substances 0.000 claims description 48
• 229960002448 dasatinib Drugs 0.000 claims description 48
• 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 47
• 239000002552 dosage form Substances 0.000 claims description 43
• QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 43
• 206010014733 Endometrial cancer Diseases 0.000 claims description 42
• 206010014759 Endometrial neoplasm Diseases 0.000 claims description 42
• 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 39
• KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims description 39
• 229960002411 imatinib Drugs 0.000 claims description 39
• 239000005536 L01XE08 - Nilotinib Substances 0.000 claims description 38
• 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 claims description 38
• 229960001346 nilotinib Drugs 0.000 claims description 38
• HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 claims description 38
• ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims description 34
• 229960002930 sirolimus Drugs 0.000 claims description 34
• AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 32
• 208000026310 Breast neoplasm Diseases 0.000 claims description 30
• 206010006187 Breast cancer Diseases 0.000 claims description 29
• 206010035226 Plasma cell myeloma Diseases 0.000 claims description 28
• 208000005718 Stomach Neoplasms Diseases 0.000 claims description 27
• 206010017758 gastric cancer Diseases 0.000 claims description 27
• 201000011549 stomach cancer Diseases 0.000 claims description 27
• 208000034578 Multiple myelomas Diseases 0.000 claims description 22
• 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 22
• 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 21
• 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 21
• 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 claims description 21
• ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 claims description 20
• 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 claims description 20
• 206010060862 Prostate cancer Diseases 0.000 claims description 20
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 20
• 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 20
• 206010005003 Bladder cancer Diseases 0.000 claims description 19
• 102000001393 Platelet-Derived Growth Factor alpha Receptor Human genes 0.000 claims description 19
• 108010068588 Platelet-Derived Growth Factor alpha Receptor Proteins 0.000 claims description 19
• 201000005112 urinary bladder cancer Diseases 0.000 claims description 19
• CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 claims description 18
• 229960000235 temsirolimus Drugs 0.000 claims description 18
• 206010009944 Colon cancer Diseases 0.000 claims description 17
• HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 claims description 17
• 229960005167 everolimus Drugs 0.000 claims description 17
• 208000005017 glioblastoma Diseases 0.000 claims description 17
• QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 claims description 16
• 230000003463 hyperproliferative effect Effects 0.000 claims description 15
• 208000020816 lung neoplasm Diseases 0.000 claims description 15
• MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 claims description 14
• 239000002147 L01XE04 - Sunitinib Substances 0.000 claims description 14
• 239000005511 L01XE05 - Sorafenib Substances 0.000 claims description 14
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 14
• 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 14
• 208000035269 cancer or benign tumor Diseases 0.000 claims description 14
• 208000029742 colonic neoplasm Diseases 0.000 claims description 14
• 201000005202 lung cancer Diseases 0.000 claims description 14
• 229960003787 sorafenib Drugs 0.000 claims description 14
• 229960001796 sunitinib Drugs 0.000 claims description 14
• WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 claims description 14
• 239000007787 solid Substances 0.000 claims description 13
• 208000008839 Kidney Neoplasms Diseases 0.000 claims description 12
• 206010038389 Renal cancer Diseases 0.000 claims description 12
• 201000010982 kidney cancer Diseases 0.000 claims description 12
• 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 11
• 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 11
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
• 229940124674 VEGF-R inhibitor Drugs 0.000 claims description 9
• 239000005557 antagonist Substances 0.000 claims description 9
• 229960000397 bevacizumab Drugs 0.000 claims description 9
• JROFGZPOBKIAEW-HAQNSBGRSA-N chembl3120215 Chemical compound N1C=2C(OC)=CC=CC=2C=C1C(=C1C(N)=NC=NN11)N=C1[C@H]1CC[C@H](C(O)=O)CC1 JROFGZPOBKIAEW-HAQNSBGRSA-N 0.000 claims description 9
• CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 claims description 9
• 229950009819 zotarolimus Drugs 0.000 claims description 9
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 8
• IMXHGCRIEAKIBU-UHFFFAOYSA-N 4-[6-[4-(methoxycarbonylamino)phenyl]-4-(4-morpholinyl)-1-pyrazolo[3,4-d]pyrimidinyl]-1-piperidinecarboxylic acid methyl ester Chemical compound C1=CC(NC(=O)OC)=CC=C1C1=NC(N2CCOCC2)=C(C=NN2C3CCN(CC3)C(=O)OC)C2=N1 IMXHGCRIEAKIBU-UHFFFAOYSA-N 0.000 claims description 7
• KVLFRAWTRWDEDF-IRXDYDNUSA-N AZD-8055 Chemical compound C1=C(CO)C(OC)=CC=C1C1=CC=C(C(=NC(=N2)N3[C@H](COCC3)C)N3[C@H](COCC3)C)C2=N1 KVLFRAWTRWDEDF-IRXDYDNUSA-N 0.000 claims description 7
• RFSMUFRPPYDYRD-CALCHBBNSA-N Ku-0063794 Chemical compound C1=C(CO)C(OC)=CC=C1C1=CC=C(C(=NC(=N2)N3C[C@@H](C)O[C@@H](C)C3)N3CCOCC3)C2=N1 RFSMUFRPPYDYRD-CALCHBBNSA-N 0.000 claims description 7
• JOGKUKXHTYWRGZ-UHFFFAOYSA-N dactolisib Chemical compound O=C1N(C)C2=CN=C3C=CC(C=4C=C5C=CC=CC5=NC=4)=CC3=C2N1C1=CC=C(C(C)(C)C#N)C=C1 JOGKUKXHTYWRGZ-UHFFFAOYSA-N 0.000 claims description 7
• 229950006418 dactolisib Drugs 0.000 claims description 7
• 230000009826 neoplastic cell growth Effects 0.000 claims description 7
• RGHYDLZMTYDBDT-UHFFFAOYSA-N 2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)-7-pyrido[2,3-d]pyrimidinone Chemical compound O=C1N(CC)C2=NC(N)=NC(C)=C2C=C1C=1C=CNN=1 RGHYDLZMTYDBDT-UHFFFAOYSA-N 0.000 claims description 6
• HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 claims description 6
• HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 claims description 6
• CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 claims description 6
• 210000004214 philadelphia chromosome Anatomy 0.000 claims description 4
• 239000007902 hard capsule Substances 0.000 claims description 3
• 239000007901 soft capsule Substances 0.000 claims description 3
• 239000007892 solid unit dosage form Substances 0.000 claims description 3
• 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 claims 1
• 239000002831 pharmacologic agent Substances 0.000 claims 1
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 abstract description 4
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
• 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 abstract 1
• 210000004027 cell Anatomy 0.000 description 309
• 230000000694 effects Effects 0.000 description 96
• 230000002354 daily effect Effects 0.000 description 85
• 230000035772 mutation Effects 0.000 description 78
• 230000005764 inhibitory process Effects 0.000 description 72
• 239000003112 inhibitor Substances 0.000 description 56
• 108091000080 Phosphotransferase Proteins 0.000 description 52
• 102000020233 phosphotransferase Human genes 0.000 description 52
• BUROJSBIWGDYCN-GAUTUEMISA-N AP 23573 Chemical compound C1C[C@@H](OP(C)(C)=O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 BUROJSBIWGDYCN-GAUTUEMISA-N 0.000 description 44
• 229960001302 ridaforolimus Drugs 0.000 description 44
• 150000001875 compounds Chemical class 0.000 description 42
• 238000004458 analytical method Methods 0.000 description 41
• 102100022596 Tyrosine-protein kinase ABL1 Human genes 0.000 description 40
• 101000823316 Homo sapiens Tyrosine-protein kinase ABL1 Proteins 0.000 description 36
• 239000003814 drug Substances 0.000 description 36
• 108010003374 fms-Like Tyrosine Kinase 3 Proteins 0.000 description 36
• 101000783817 Agaricus bisporus lectin Proteins 0.000 description 34
• 101000588130 Homo sapiens Microsomal triglyceride transfer protein large subunit Proteins 0.000 description 34
• 208000032839 leukemia Diseases 0.000 description 34
• 241000699670 Mus sp. Species 0.000 description 33
• 229940079593 drug Drugs 0.000 description 32
• 230000026731 phosphorylation Effects 0.000 description 32
• 238000006366 phosphorylation reaction Methods 0.000 description 32
• 230000004083 survival effect Effects 0.000 description 30
• 239000003981 vehicle Substances 0.000 description 29
• 230000011664 signaling Effects 0.000 description 28
• 230000002401 inhibitory effect Effects 0.000 description 27
• 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 26
• 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 26
• 238000001516 cell proliferation assay Methods 0.000 description 26
• 230000001965 increasing effect Effects 0.000 description 25
• 101150118364 Crkl gene Proteins 0.000 description 24
• 238000003119 immunoblot Methods 0.000 description 24
• 230000012010 growth Effects 0.000 description 23
• 238000003556 assay Methods 0.000 description 22
• 238000000338 in vitro Methods 0.000 description 22
• 229940043355 kinase inhibitor Drugs 0.000 description 22
• 239000003757 phosphotransferase inhibitor Substances 0.000 description 22
• 230000004614 tumor growth Effects 0.000 description 22
• 238000002474 experimental method Methods 0.000 description 21
• 238000001727 in vivo Methods 0.000 description 21
• 230000004663 cell proliferation Effects 0.000 description 19
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
• 108091008794 FGF receptors Proteins 0.000 description 17
• 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 16
• 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 16
• 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 15
• 210000004369 blood Anatomy 0.000 description 15
• 239000008280 blood Substances 0.000 description 15
• 238000002648 combination therapy Methods 0.000 description 15
• 230000009036 growth inhibition Effects 0.000 description 15
• 230000003285 pharmacodynamic effect Effects 0.000 description 15
• 208000034038 Pathologic Neovascularization Diseases 0.000 description 14
• 208000007502 anemia Diseases 0.000 description 14
• 210000005087 mononuclear cell Anatomy 0.000 description 14
• 108090000623 proteins and genes Proteins 0.000 description 14
• 239000003826 tablet Substances 0.000 description 14
• 239000002775 capsule Substances 0.000 description 13
• 102000004169 proteins and genes Human genes 0.000 description 13
• 201000004681 Psoriasis Diseases 0.000 description 12
• REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 12
• 230000033115 angiogenesis Effects 0.000 description 12
• 230000010261 cell growth Effects 0.000 description 12
• 238000001990 intravenous administration Methods 0.000 description 12
• 230000035755 proliferation Effects 0.000 description 12
• 206010039073 rheumatoid arthritis Diseases 0.000 description 12
• 208000004860 Blast Crisis Diseases 0.000 description 11
• 208000008589 Obesity Diseases 0.000 description 11
• 208000037976 chronic inflammation Diseases 0.000 description 11
• 230000006020 chronic inflammation Effects 0.000 description 11
• 208000002780 macular degeneration Diseases 0.000 description 11
• 235000020824 obesity Nutrition 0.000 description 11
• 230000004044 response Effects 0.000 description 11
• 201000001320 Atherosclerosis Diseases 0.000 description 10
• 241001465754 Metazoa Species 0.000 description 10
• 108010029477 STAT5 Transcription Factor Proteins 0.000 description 10
• 102000001712 STAT5 Transcription Factor Human genes 0.000 description 10
• 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 10
• 210000000481 breast Anatomy 0.000 description 10
• 239000003120 macrolide antibiotic agent Substances 0.000 description 10
• 238000002703 mutagenesis Methods 0.000 description 10
• 231100000350 mutagenesis Toxicity 0.000 description 10
• 208000024172 Cardiovascular disease Diseases 0.000 description 9
• 206010012689 Diabetic retinopathy Diseases 0.000 description 9
• 206010061535 Ovarian neoplasm Diseases 0.000 description 9
• 230000002159 abnormal effect Effects 0.000 description 9
• 230000005856 abnormality Effects 0.000 description 9
• 150000002148 esters Chemical class 0.000 description 9
• 201000001441 melanoma Diseases 0.000 description 9
• 210000002307 prostate Anatomy 0.000 description 9
• 230000035899 viability Effects 0.000 description 9
• 101150018665 MAPK3 gene Proteins 0.000 description 8
• 206010061902 Pancreatic neoplasm Diseases 0.000 description 8
• 101100331535 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) DIB1 gene Proteins 0.000 description 8
• 239000012458 free base Substances 0.000 description 8
• 208000014829 head and neck neoplasm Diseases 0.000 description 8
• 238000001802 infusion Methods 0.000 description 8
• 210000003734 kidney Anatomy 0.000 description 8
• 210000004072 lung Anatomy 0.000 description 8
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
• 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 8
• 238000003305 oral gavage Methods 0.000 description 8
• 210000001672 ovary Anatomy 0.000 description 8
• 210000000496 pancreas Anatomy 0.000 description 8
• 208000008443 pancreatic carcinoma Diseases 0.000 description 8
• 230000001575 pathological effect Effects 0.000 description 8
• 230000036470 plasma concentration Effects 0.000 description 8
• 238000009097 single-agent therapy Methods 0.000 description 8
• 239000000243 solution Substances 0.000 description 8
• 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 8
• 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 8
• OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 7
• 206010025323 Lymphomas Diseases 0.000 description 7
• 206010033128 Ovarian cancer Diseases 0.000 description 7
• 239000000872 buffer Substances 0.000 description 7
• 150000004657 carbamic acid derivatives Chemical class 0.000 description 7
• 230000003833 cell viability Effects 0.000 description 7
• 239000003153 chemical reaction reagent Substances 0.000 description 7
• 238000010293 colony formation assay Methods 0.000 description 7
• 230000001419 dependent effect Effects 0.000 description 7
• 239000000945 filler Substances 0.000 description 7
• 210000003128 head Anatomy 0.000 description 7
• 150000003840 hydrochlorides Chemical class 0.000 description 7
• 238000005259 measurement Methods 0.000 description 7
• 239000002609 medium Substances 0.000 description 7
• 210000003739 neck Anatomy 0.000 description 7
• 108091008598 receptor tyrosine kinases Proteins 0.000 description 7
• 102000027426 receptor tyrosine kinases Human genes 0.000 description 7
• 210000002784 stomach Anatomy 0.000 description 7
• 238000007920 subcutaneous administration Methods 0.000 description 7
• 238000006467 substitution reaction Methods 0.000 description 7
• 208000024891 symptom Diseases 0.000 description 7
• 230000002195 synergetic effect Effects 0.000 description 7
• 238000012360 testing method Methods 0.000 description 7
• OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 7
• 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 6
• 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 6
• 102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 description 6
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
• 208000002250 Hematologic Neoplasms Diseases 0.000 description 6
• 101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 description 6
• 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 6
• 208000007766 Kaposi sarcoma Diseases 0.000 description 6
• 241000699666 Mus <mouse, genus> Species 0.000 description 6
• 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 6
• 102000001253 Protein Kinase Human genes 0.000 description 6
• ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 description 6
• HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 description 6
• 230000008901 benefit Effects 0.000 description 6
• MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 6
• 238000000021 kinase assay Methods 0.000 description 6
• 210000004185 liver Anatomy 0.000 description 6
• 201000000050 myeloid neoplasm Diseases 0.000 description 6
• 208000002154 non-small cell lung carcinoma Diseases 0.000 description 6
• 230000037361 pathway Effects 0.000 description 6
• 230000003389 potentiating effect Effects 0.000 description 6
• 108060006633 protein kinase Proteins 0.000 description 6
• 235000005875 quercetin Nutrition 0.000 description 6
• 229960001285 quercetin Drugs 0.000 description 6
• 102000005962 receptors Human genes 0.000 description 6
• 108020003175 receptors Proteins 0.000 description 6
• 230000002829 reductive effect Effects 0.000 description 6
• 239000000758 substrate Substances 0.000 description 6
• 230000002459 sustained effect Effects 0.000 description 6
• 210000001685 thyroid gland Anatomy 0.000 description 6
• 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 6
• YYSFXUWWPNHNAZ-PKJQJFMNSA-N umirolimus Chemical compound C1[C@@H](OC)[C@H](OCCOCC)CC[C@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 YYSFXUWWPNHNAZ-PKJQJFMNSA-N 0.000 description 6
• 229920001817 Agar Polymers 0.000 description 5
• 208000032800 BCR-ABL1 positive blast phase chronic myelogenous leukemia Diseases 0.000 description 5
• 229940118364 Bcr-Abl inhibitor Drugs 0.000 description 5
• 208000023611 Burkitt leukaemia Diseases 0.000 description 5
• 208000011691 Burkitt lymphomas Diseases 0.000 description 5
• 201000008808 Fibrosarcoma Diseases 0.000 description 5
• 208000032612 Glial tumor Diseases 0.000 description 5
• 201000010915 Glioblastoma multiforme Diseases 0.000 description 5
• 206010018338 Glioma Diseases 0.000 description 5
• 241000124008 Mammalia Species 0.000 description 5
• 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 5
• 102000014160 PTEN Phosphohydrolase Human genes 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
• 208000000453 Skin Neoplasms Diseases 0.000 description 5
• 208000024770 Thyroid neoplasm Diseases 0.000 description 5
• 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 5
• 230000004913 activation Effects 0.000 description 5
• 239000008272 agar Substances 0.000 description 5
• 230000000259 anti-tumor effect Effects 0.000 description 5
• 201000010881 cervical cancer Diseases 0.000 description 5
• 210000003679 cervix uteri Anatomy 0.000 description 5
• 230000008859 change Effects 0.000 description 5
• 239000003795 chemical substances by application Substances 0.000 description 5
• 238000005516 engineering process Methods 0.000 description 5
• 210000003743 erythrocyte Anatomy 0.000 description 5
• 108020001507 fusion proteins Proteins 0.000 description 5
• 102000037865 fusion proteins Human genes 0.000 description 5
• 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 5
• 201000010536 head and neck cancer Diseases 0.000 description 5
• 230000002489 hematologic effect Effects 0.000 description 5
• 230000006698 induction Effects 0.000 description 5
• 238000010899 nucleation Methods 0.000 description 5
• 201000008968 osteosarcoma Diseases 0.000 description 5
• 230000002085 persistent effect Effects 0.000 description 5
• PHXJVRSECIGDHY-UHFFFAOYSA-N ponatinib Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2N3N=CC=CC3=NC=2)=C1 PHXJVRSECIGDHY-UHFFFAOYSA-N 0.000 description 5
• 230000009467 reduction Effects 0.000 description 5
• 238000012216 screening Methods 0.000 description 5
• 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 5
• 206010041823 squamous cell carcinoma Diseases 0.000 description 5
• 208000001608 teratocarcinoma Diseases 0.000 description 5
• 210000003932 urinary bladder Anatomy 0.000 description 5
• 230000003442 weekly effect Effects 0.000 description 5
• 238000001262 western blot Methods 0.000 description 5
• QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 5
• QDLHCMPXEPAAMD-UHFFFAOYSA-N wortmannin Natural products COCC1OC(=O)C2=COC(C3=O)=C2C1(C)C1=C3C2CCC(=O)C2(C)CC1OC(C)=O QDLHCMPXEPAAMD-UHFFFAOYSA-N 0.000 description 5
• WCWUXEGQKLTGDX-LLVKDONJSA-N (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol Chemical compound C1=C2NC(C)=CC2=C(F)C(OC2=NC=NN3C=C(C(=C32)C)OC[C@H](O)C)=C1 WCWUXEGQKLTGDX-LLVKDONJSA-N 0.000 description 4
• 208000004736 B-Cell Leukemia Diseases 0.000 description 4
• 206010058314 Dysplasia Diseases 0.000 description 4
• 229920001917 Ficoll Polymers 0.000 description 4
• 208000022072 Gallbladder Neoplasms Diseases 0.000 description 4
• 239000002137 L01XE24 - Ponatinib Substances 0.000 description 4
• 241000699660 Mus musculus Species 0.000 description 4
• FUSGACRLAFQQRL-UHFFFAOYSA-N N-Ethyl-N-nitrosourea Chemical compound CCN(N=O)C(N)=O FUSGACRLAFQQRL-UHFFFAOYSA-N 0.000 description 4
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
• 101710179684 Poly [ADP-ribose] polymerase Proteins 0.000 description 4
• 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 4
• 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 4
• 206010039491 Sarcoma Diseases 0.000 description 4
• 208000000389 T-cell leukemia Diseases 0.000 description 4
• 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 description 4
• 230000003213 activating effect Effects 0.000 description 4
• 230000006907 apoptotic process Effects 0.000 description 4
• 230000005907 cancer growth Effects 0.000 description 4
• 238000005119 centrifugation Methods 0.000 description 4
• PIQCTGMSNWUMAF-UHFFFAOYSA-N chembl522892 Chemical compound C1CN(C)CCN1C1=CC=C(NC(=N2)C=3C(NC4=CC=CC(F)=C4C=3N)=O)C2=C1 PIQCTGMSNWUMAF-UHFFFAOYSA-N 0.000 description 4
• 239000007979 citrate buffer Substances 0.000 description 4
• 230000005757 colony formation Effects 0.000 description 4
• 239000013256 coordination polymer Substances 0.000 description 4
• 238000000326 densiometry Methods 0.000 description 4
• 239000007884 disintegrant Substances 0.000 description 4
• 231100000673 dose–response relationship Toxicity 0.000 description 4
• 208000023965 endometrium neoplasm Diseases 0.000 description 4
• 238000011156 evaluation Methods 0.000 description 4
• 210000000232 gallbladder Anatomy 0.000 description 4
• 201000010175 gallbladder cancer Diseases 0.000 description 4
• 201000009277 hairy cell leukemia Diseases 0.000 description 4
• 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 description 4
• 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 4
• 229910052739 hydrogen Inorganic materials 0.000 description 4
• 239000001257 hydrogen Substances 0.000 description 4
• 210000004324 lymphatic system Anatomy 0.000 description 4
• 229940041033 macrolides Drugs 0.000 description 4
• 235000019359 magnesium stearate Nutrition 0.000 description 4
• 230000001404 mediated effect Effects 0.000 description 4
• 239000012528 membrane Substances 0.000 description 4
• 208000025113 myeloid leukemia Diseases 0.000 description 4
• 208000007538 neurilemmoma Diseases 0.000 description 4
• 229960004378 nintedanib Drugs 0.000 description 4
• XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 description 4
• 238000011580 nude mouse model Methods 0.000 description 4
• 201000002528 pancreatic cancer Diseases 0.000 description 4
• 230000008506 pathogenesis Effects 0.000 description 4
• 210000005259 peripheral blood Anatomy 0.000 description 4
• 239000011886 peripheral blood Substances 0.000 description 4
• 229960001131 ponatinib Drugs 0.000 description 4
• 230000006920 protein precipitation Effects 0.000 description 4
• 230000002441 reversible effect Effects 0.000 description 4
• 206010039667 schwannoma Diseases 0.000 description 4
• 201000000849 skin cancer Diseases 0.000 description 4
• 239000011550 stock solution Substances 0.000 description 4
• 229960005322 streptomycin Drugs 0.000 description 4
• 239000000126 substance Substances 0.000 description 4
• 208000011580 syndromic disease Diseases 0.000 description 4
• 238000002560 therapeutic procedure Methods 0.000 description 4
• 201000002510 thyroid cancer Diseases 0.000 description 4
• 230000005945 translocation Effects 0.000 description 4
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
• 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 3
• 206010003571 Astrocytoma Diseases 0.000 description 3
• 102000047934 Caspase-3/7 Human genes 0.000 description 3
• 108700037887 Caspase-3/7 Proteins 0.000 description 3
• 208000001333 Colorectal Neoplasms Diseases 0.000 description 3
• 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 3
• 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 3
• 102000004190 Enzymes Human genes 0.000 description 3
• 108090000790 Enzymes Proteins 0.000 description 3
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
• 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 3
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
• ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
• 229930182816 L-glutamine Natural products 0.000 description 3
• 108091054455 MAP kinase family Proteins 0.000 description 3
• 102000043136 MAP kinase family Human genes 0.000 description 3
• 238000000719 MTS assay Methods 0.000 description 3
• 231100000070 MTS assay Toxicity 0.000 description 3
• 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 3
• 206010029260 Neuroblastoma Diseases 0.000 description 3
• 102000038030 PI3Ks Human genes 0.000 description 3
• 108091007960 PI3Ks Proteins 0.000 description 3
• 229930182555 Penicillin Natural products 0.000 description 3
• 102000035195 Peptidases Human genes 0.000 description 3
• 108091005804 Peptidases Proteins 0.000 description 3
• 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 3
• 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 3
• 239000004365 Protease Substances 0.000 description 3
• 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 3
• 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 3
• 241000508269 Psidium Species 0.000 description 3
• 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 3
• 201000010208 Seminoma Diseases 0.000 description 3
• 108091008605 VEGF receptors Proteins 0.000 description 3
• 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 3
• 239000002253 acid Substances 0.000 description 3
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 3
• 230000035578 autophosphorylation Effects 0.000 description 3
• 230000015572 biosynthetic process Effects 0.000 description 3
• 238000002701 cell growth assay Methods 0.000 description 3
• 230000005754 cellular signaling Effects 0.000 description 3
• 201000007455 central nervous system cancer Diseases 0.000 description 3
• 208000025997 central nervous system neoplasm Diseases 0.000 description 3
• 208000021668 chronic eosinophilic leukemia Diseases 0.000 description 3
• 208000032852 chronic lymphocytic leukemia Diseases 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
• 210000001072 colon Anatomy 0.000 description 3
• 230000002559 cytogenic effect Effects 0.000 description 3
• 230000001472 cytotoxic effect Effects 0.000 description 3
• 230000003247 decreasing effect Effects 0.000 description 3
• 230000002950 deficient Effects 0.000 description 3
• 238000011161 development Methods 0.000 description 3
• 230000018109 developmental process Effects 0.000 description 3
• 208000035475 disorder Diseases 0.000 description 3
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 3
• 239000007888 film coating Substances 0.000 description 3
• 238000009501 film coating Methods 0.000 description 3
• 238000001943 fluorescence-activated cell sorting Methods 0.000 description 3
• 239000013022 formulation composition Substances 0.000 description 3
• 230000006870 function Effects 0.000 description 3
• 230000004927 fusion Effects 0.000 description 3
• 229960002743 glutamine Drugs 0.000 description 3
• 230000003394 haemopoietic effect Effects 0.000 description 3
• 201000005787 hematologic cancer Diseases 0.000 description 3
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
• FHBSGPWHCCIQPG-UHFFFAOYSA-N hydroxy-methyl-oxo-sulfanylidene-$l^{6}-sulfane Chemical compound CS(S)(=O)=O FHBSGPWHCCIQPG-UHFFFAOYSA-N 0.000 description 3
• 210000002429 large intestine Anatomy 0.000 description 3
• 238000011068 loading method Methods 0.000 description 3
• 239000000314 lubricant Substances 0.000 description 3
• 208000026037 malignant tumor of neck Diseases 0.000 description 3
• 239000000463 material Substances 0.000 description 3
• 231100000682 maximum tolerated dose Toxicity 0.000 description 3
• 201000008806 mesenchymal cell neoplasm Diseases 0.000 description 3
• 229920000609 methyl cellulose Polymers 0.000 description 3
• 239000001923 methylcellulose Substances 0.000 description 3
• 238000002156 mixing Methods 0.000 description 3
• 238000010172 mouse model Methods 0.000 description 3
• 210000000056 organ Anatomy 0.000 description 3
• 239000013610 patient sample Substances 0.000 description 3
• 229940049954 penicillin Drugs 0.000 description 3
• 230000002035 prolonged effect Effects 0.000 description 3
• 201000009410 rhabdomyosarcoma Diseases 0.000 description 3
• 239000000523 sample Substances 0.000 description 3
• 238000013207 serial dilution Methods 0.000 description 3
• 239000012679 serum free medium Substances 0.000 description 3
• 210000001519 tissue Anatomy 0.000 description 3
• 210000003462 vein Anatomy 0.000 description 3
• QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
• LDDHMKANNXWUAK-UHFFFAOYSA-N 3-iodo-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C=C1I LDDHMKANNXWUAK-UHFFFAOYSA-N 0.000 description 2
• XXJWYDDUDKYVKI-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)N=CN=C2C=C1OCCCN1CCCC1 XXJWYDDUDKYVKI-UHFFFAOYSA-N 0.000 description 2
• UZOVYGYOLBIAJR-UHFFFAOYSA-N 4-isocyanato-4'-methyldiphenylmethane Chemical compound C1=CC(C)=CC=C1CC1=CC=C(N=C=O)C=C1 UZOVYGYOLBIAJR-UHFFFAOYSA-N 0.000 description 2
• 101001082110 Acanthamoeba polyphaga mimivirus Eukaryotic translation initiation factor 4E homolog Proteins 0.000 description 2
• WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 2
• CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
• 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 2
• 102000011727 Caspases Human genes 0.000 description 2
• 108010076667 Caspases Proteins 0.000 description 2
• 206010008342 Cervix carcinoma Diseases 0.000 description 2
• 108020004414 DNA Proteins 0.000 description 2
• 101001082109 Danio rerio Eukaryotic translation initiation factor 4E-1B Proteins 0.000 description 2
• 238000001061 Dunnett's test Methods 0.000 description 2
• 208000010201 Exanthema Diseases 0.000 description 2
• 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 2
• 208000017604 Hodgkin disease Diseases 0.000 description 2
• 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
• 241000282412 Homo Species 0.000 description 2
• 108010002386 Interleukin-3 Proteins 0.000 description 2
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
• 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
• 206010027406 Mesothelioma Diseases 0.000 description 2
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
• 239000000020 Nitrocellulose Substances 0.000 description 2
• 108700020796 Oncogene Proteins 0.000 description 2
• 208000002193 Pain Diseases 0.000 description 2
• 206010033645 Pancreatitis Diseases 0.000 description 2
• 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 2
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
• OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
• 108091008611 Protein Kinase B Proteins 0.000 description 2
• 239000012980 RPMI-1640 medium Substances 0.000 description 2
• 238000011579 SCID mouse model Methods 0.000 description 2
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
• 108010090091 TIE-2 Receptor Proteins 0.000 description 2
• 102000012753 TIE-2 Receptor Human genes 0.000 description 2
• GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
• 238000002441 X-ray diffraction Methods 0.000 description 2
• 230000001154 acute effect Effects 0.000 description 2
• 230000002411 adverse Effects 0.000 description 2
• 230000000719 anti-leukaemic effect Effects 0.000 description 2
• 238000013459 approach Methods 0.000 description 2
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
• 201000000053 blastoma Diseases 0.000 description 2
• 238000009835 boiling Methods 0.000 description 2
• 210000001185 bone marrow Anatomy 0.000 description 2
• MKQAYNDYRGDZMH-UHFFFAOYSA-N carbamimidoyl carbamate Chemical class NC(=N)OC(N)=O MKQAYNDYRGDZMH-UHFFFAOYSA-N 0.000 description 2
• 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
• 229960002412 cediranib Drugs 0.000 description 2
• 238000000423 cell based assay Methods 0.000 description 2
• 230000022131 cell cycle Effects 0.000 description 2
• 239000013592 cell lysate Substances 0.000 description 2
• 210000003169 central nervous system Anatomy 0.000 description 2
• 238000006243 chemical reaction Methods 0.000 description 2
• 230000001684 chronic effect Effects 0.000 description 2
• 238000003776 cleavage reaction Methods 0.000 description 2
• 239000013078 crystal Substances 0.000 description 2
• 238000012866 crystallographic experiment Methods 0.000 description 2
• 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 2
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
• 231100000433 cytotoxic Toxicity 0.000 description 2
• 230000001934 delay Effects 0.000 description 2
• 238000001212 derivatisation Methods 0.000 description 2
• 206010012601 diabetes mellitus Diseases 0.000 description 2
• 238000003745 diagnosis Methods 0.000 description 2
• 201000008184 embryoma Diseases 0.000 description 2
• 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 2
• 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 2
• 150000002170 ethers Chemical class 0.000 description 2
• 230000003203 everyday effect Effects 0.000 description 2
• 201000005884 exanthem Diseases 0.000 description 2
• 229940125829 fibroblast growth factor receptor inhibitor Drugs 0.000 description 2
• MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 2
• 238000009472 formulation Methods 0.000 description 2
• 102000006602 glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 2
• 210000003958 hematopoietic stem cell Anatomy 0.000 description 2
• 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
• 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
• IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
• 238000011534 incubation Methods 0.000 description 2
• 230000006882 induction of apoptosis Effects 0.000 description 2
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
• JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
• 229960001021 lactose monohydrate Drugs 0.000 description 2
• 239000012160 loading buffer Substances 0.000 description 2
• 208000003747 lymphoid leukemia Diseases 0.000 description 2
• 239000006166 lysate Substances 0.000 description 2
• 230000003211 malignant effect Effects 0.000 description 2
• 210000004379 membrane Anatomy 0.000 description 2
• 230000004048 modification Effects 0.000 description 2
• 238000012986 modification Methods 0.000 description 2
• 210000000214 mouth Anatomy 0.000 description 2
• 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 2
• 230000035407 negative regulation of cell proliferation Effects 0.000 description 2
• 229920001220 nitrocellulos Polymers 0.000 description 2
• 238000001543 one-way ANOVA Methods 0.000 description 2
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
• 230000007170 pathology Effects 0.000 description 2
• 210000001428 peripheral nervous system Anatomy 0.000 description 2
• 201000005528 peripheral nervous system neoplasm Diseases 0.000 description 2
• 230000000144 pharmacologic effect Effects 0.000 description 2
• 229910052698 phosphorus Inorganic materials 0.000 description 2
• 239000011574 phosphorus Substances 0.000 description 2
• 230000004962 physiological condition Effects 0.000 description 2
• BWTNNZPNKQIADY-UHFFFAOYSA-N ponatinib hydrochloride Chemical compound Cl.C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2N3N=CC=CC3=NC=2)=C1 BWTNNZPNKQIADY-UHFFFAOYSA-N 0.000 description 2
• 238000004393 prognosis Methods 0.000 description 2
• 238000011321 prophylaxis Methods 0.000 description 2
• 208000023958 prostate neoplasm Diseases 0.000 description 2
• 239000003531 protein hydrolysate Substances 0.000 description 2
• 206010037844 rash Diseases 0.000 description 2
• 238000011160 research Methods 0.000 description 2
• 210000002345 respiratory system Anatomy 0.000 description 2
• 238000003757 reverse transcription PCR Methods 0.000 description 2
• 238000012552 review 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
• 230000007017 scission Effects 0.000 description 2
• 208000011571 secondary malignant neoplasm Diseases 0.000 description 2
• 230000035945 sensitivity Effects 0.000 description 2
• 230000019491 signal transduction Effects 0.000 description 2
• 229940079832 sodium starch glycolate Drugs 0.000 description 2
• 239000008109 sodium starch glycolate Substances 0.000 description 2
• 229920003109 sodium starch glycolate Polymers 0.000 description 2
• 210000004872 soft tissue Anatomy 0.000 description 2
• 239000007909 solid dosage form Substances 0.000 description 2
• 239000002904 solvent Substances 0.000 description 2
• 241000894007 species Species 0.000 description 2
• 238000011272 standard treatment Methods 0.000 description 2
• 210000000130 stem cell Anatomy 0.000 description 2
• TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
• 230000001629 suppression Effects 0.000 description 2
• 239000000725 suspension Substances 0.000 description 2
• 238000003786 synthesis reaction Methods 0.000 description 2
• 210000001550 testis Anatomy 0.000 description 2
• 210000004881 tumor cell Anatomy 0.000 description 2
• 210000004291 uterus Anatomy 0.000 description 2
• DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
• BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
• PTBDIHRZYDMNKB-UHFFFAOYSA-N 2,2-Bis(hydroxymethyl)propionic acid Chemical compound OCC(C)(CO)C(O)=O PTBDIHRZYDMNKB-UHFFFAOYSA-N 0.000 description 1
• LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
• NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
• FSPQCTGGIANIJZ-UHFFFAOYSA-N 2-[[(3,4-dimethoxyphenyl)-oxomethyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)NC1=C(C(N)=O)C(CCCC2)=C2S1 FSPQCTGGIANIJZ-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
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
• YYSFXUWWPNHNAZ-OSDRTFJJSA-N 851536-75-9 Chemical compound C1[C@@H](OC)[C@H](OCCOCC)CC[C@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CCC2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 YYSFXUWWPNHNAZ-OSDRTFJJSA-N 0.000 description 1
• 208000002008 AIDS-Related Lymphoma Diseases 0.000 description 1
• ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 1
• ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 1
• 230000007730 Akt signaling Effects 0.000 description 1
• 108700028369 Alleles Proteins 0.000 description 1
• GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
• 108090000672 Annexin A5 Proteins 0.000 description 1
• 102000004121 Annexin A5 Human genes 0.000 description 1
• 208000006820 Arthralgia Diseases 0.000 description 1
• 108090000433 Aurora kinases Proteins 0.000 description 1
• 102000003989 Aurora kinases Human genes 0.000 description 1
• 238000000035 BCA protein assay Methods 0.000 description 1
• 229940124290 BCR-ABL tyrosine kinase inhibitor Drugs 0.000 description 1
• 206010061692 Benign muscle neoplasm Diseases 0.000 description 1
• 239000005711 Benzoic acid Substances 0.000 description 1
• 241000283690 Bos taurus Species 0.000 description 1
• 208000006274 Brain Stem Neoplasms Diseases 0.000 description 1
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
• 201000009030 Carcinoma Diseases 0.000 description 1
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
• 206010010144 Completed suicide Diseases 0.000 description 1
• 102100029375 Crk-like protein Human genes 0.000 description 1
• 102000003910 Cyclin D Human genes 0.000 description 1
• 108090000259 Cyclin D Proteins 0.000 description 1
• 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
• 108010025454 Cyclin-Dependent Kinase 5 Proteins 0.000 description 1
• 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 1
• 102100032857 Cyclin-dependent kinase 1 Human genes 0.000 description 1
• 101710106279 Cyclin-dependent kinase 1 Proteins 0.000 description 1
• 102100023263 Cyclin-dependent kinase 10 Human genes 0.000 description 1
• 102100036329 Cyclin-dependent kinase 3 Human genes 0.000 description 1
• 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 1
• 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 description 1
• 102100026810 Cyclin-dependent kinase 7 Human genes 0.000 description 1
• 102100024456 Cyclin-dependent kinase 8 Human genes 0.000 description 1
• 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 description 1
• 108090000266 Cyclin-dependent kinases Proteins 0.000 description 1
• 102000003903 Cyclin-dependent kinases Human genes 0.000 description 1
• 102100026805 Cyclin-dependent-like kinase 5 Human genes 0.000 description 1
• 201000005171 Cystadenoma Diseases 0.000 description 1
• 101100481408 Danio rerio tie2 gene Proteins 0.000 description 1
• 101100314281 Danio rerio trappc11 gene Proteins 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
• 235000017274 Diospyros sandwicensis Nutrition 0.000 description 1
• 206010059866 Drug resistance Diseases 0.000 description 1
• 101150000637 EOL1 gene Proteins 0.000 description 1
• 102100030011 Endoribonuclease Human genes 0.000 description 1
• 101710199605 Endoribonuclease Proteins 0.000 description 1
• 206010014950 Eosinophilia Diseases 0.000 description 1
• 241000283073 Equus caballus Species 0.000 description 1
• 241000588724 Escherichia coli Species 0.000 description 1
• 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
• 101150036586 FES gene Proteins 0.000 description 1
• 101150017750 FGFRL1 gene Proteins 0.000 description 1
• 208000000164 Familial pancreatic carcinoma Diseases 0.000 description 1
• 241000282326 Felis catus Species 0.000 description 1
• 101150040897 Fgr gene Proteins 0.000 description 1
• 102100026149 Fibroblast growth factor receptor-like 1 Human genes 0.000 description 1
• 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
• 108010010803 Gelatin Proteins 0.000 description 1
• 208000034951 Genetic Translocation Diseases 0.000 description 1
• 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
• 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
• 102000009465 Growth Factor Receptors Human genes 0.000 description 1
• 108010009202 Growth Factor Receptors Proteins 0.000 description 1
• 101000919315 Homo sapiens Crk-like protein Proteins 0.000 description 1
• 101000908138 Homo sapiens Cyclin-dependent kinase 10 Proteins 0.000 description 1
• 101000715946 Homo sapiens Cyclin-dependent kinase 3 Proteins 0.000 description 1
• 101000911952 Homo sapiens Cyclin-dependent kinase 7 Proteins 0.000 description 1
• 101000980937 Homo sapiens Cyclin-dependent kinase 8 Proteins 0.000 description 1
• 101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 description 1
• 101000596894 Homo sapiens High affinity nerve growth factor receptor Proteins 0.000 description 1
• 101000878540 Homo sapiens Protein-tyrosine kinase 2-beta Proteins 0.000 description 1
• 101000850794 Homo sapiens Tropomyosin alpha-3 chain Proteins 0.000 description 1
• 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 description 1
• AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical class ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
• 102000004877 Insulin Human genes 0.000 description 1
• 108090001061 Insulin Proteins 0.000 description 1
• 108010001127 Insulin Receptor Proteins 0.000 description 1
• 102100036721 Insulin receptor Human genes 0.000 description 1
• 108010002350 Interleukin-2 Proteins 0.000 description 1
• 102000007330 LDL Lipoproteins Human genes 0.000 description 1
• 108010007622 LDL Lipoproteins Proteins 0.000 description 1
• 241000282838 Lama Species 0.000 description 1
• 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 1
• 206010024305 Leukaemia monocytic Diseases 0.000 description 1
• 102000004882 Lipase Human genes 0.000 description 1
• 108090001060 Lipase Proteins 0.000 description 1
• 239000004367 Lipase Substances 0.000 description 1
• 229940110339 Long-acting muscarinic antagonist Drugs 0.000 description 1
• 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
• 206010025312 Lymphoma AIDS related Diseases 0.000 description 1
• 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 1
• 206010027476 Metastases Diseases 0.000 description 1
• 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
• 208000003445 Mouth Neoplasms Diseases 0.000 description 1
• 241001529936 Murinae Species 0.000 description 1
• 101100268066 Mus musculus Zap70 gene Proteins 0.000 description 1
• 208000036503 Myeloid/lymphoid neoplasm associated with FGFR1 rearrangement Diseases 0.000 description 1
• 201000004458 Myoma Diseases 0.000 description 1
• IKMDFBPHZNJCSN-UHFFFAOYSA-N Myricetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC(O)=C(O)C(O)=C1 IKMDFBPHZNJCSN-UHFFFAOYSA-N 0.000 description 1
• 206010028813 Nausea Diseases 0.000 description 1
• 238000011887 Necropsy Methods 0.000 description 1
• 206010029098 Neoplasm skin Diseases 0.000 description 1
• 208000008636 Neoplastic Processes Diseases 0.000 description 1
• 208000009277 Neuroectodermal Tumors Diseases 0.000 description 1
• 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
• 108091028043 Nucleic acid sequence Proteins 0.000 description 1
• 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
• 241000283973 Oryctolagus cuniculus Species 0.000 description 1
• 101100381429 Oryza sativa subsp. japonica BADH2 gene Proteins 0.000 description 1
• 235000021314 Palmitic acid Nutrition 0.000 description 1
• 206010034133 Pathogen resistance Diseases 0.000 description 1
• 241001494479 Pecora Species 0.000 description 1
• 241000009328 Perro Species 0.000 description 1
• 208000007913 Pituitary Neoplasms Diseases 0.000 description 1
• 239000004698 Polyethylene Substances 0.000 description 1
• 241000288906 Primates Species 0.000 description 1
• OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
• 108010029485 Protein Isoforms Proteins 0.000 description 1
• 102000001708 Protein Isoforms Human genes 0.000 description 1
• 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 1
• 102100037787 Protein-tyrosine kinase 2-beta Human genes 0.000 description 1
• 239000012083 RIPA buffer Substances 0.000 description 1
• 241000700159 Rattus Species 0.000 description 1
• 101710151245 Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 1
• 208000015634 Rectal Neoplasms Diseases 0.000 description 1
• 206010038270 Refractory anaemia with an excess of blasts Diseases 0.000 description 1
• 208000033501 Refractory anemia with excess blasts Diseases 0.000 description 1
• 208000032411 Refractory with Excess of Blasts Anemia Diseases 0.000 description 1
• 208000017442 Retinal disease Diseases 0.000 description 1
• 206010038923 Retinopathy Diseases 0.000 description 1
• 239000012721 SDS lysis buffer Substances 0.000 description 1
• 108060006706 SRC Proteins 0.000 description 1
• 102000001332 SRC Human genes 0.000 description 1
• 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 1
• 206010061934 Salivary gland cancer Diseases 0.000 description 1
• 208000034189 Sclerosis Diseases 0.000 description 1
• 238000012300 Sequence Analysis Methods 0.000 description 1
• 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 1
• 102100023085 Serine/threonine-protein kinase mTOR Human genes 0.000 description 1
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
• XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
• 206010041067 Small cell lung cancer Diseases 0.000 description 1
• VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
• 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
• 206010041660 Splenomegaly Diseases 0.000 description 1
• 241000187747 Streptomyces Species 0.000 description 1
• KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
• 241000282898 Sus scrofa Species 0.000 description 1
• 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 1
• 206010042971 T-cell lymphoma Diseases 0.000 description 1
• 208000027585 T-cell non-Hodgkin lymphoma Diseases 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
• 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
• 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
• 208000002495 Uterine Neoplasms Diseases 0.000 description 1
• 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 1
• 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 1
• 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
• 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
• 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
• 208000027418 Wounds and injury Diseases 0.000 description 1
• REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 description 1
• ZKHQWZAMYRWXGA-KNYAHOBESA-N [[(2r,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] dihydroxyphosphoryl hydrogen phosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)O[32P](O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KNYAHOBESA-N 0.000 description 1
• 238000010521 absorption reaction Methods 0.000 description 1
• 238000009825 accumulation Methods 0.000 description 1
• 230000009471 action Effects 0.000 description 1
• 230000006978 adaptation Effects 0.000 description 1
• 210000004100 adrenal gland Anatomy 0.000 description 1
• 238000011166 aliquoting Methods 0.000 description 1
• 125000003545 alkoxy group Chemical group 0.000 description 1
• BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
• 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
• 125000004103 aminoalkyl group Chemical group 0.000 description 1
• 210000002255 anal canal Anatomy 0.000 description 1
• 229960004977 anhydrous lactose Drugs 0.000 description 1
• 238000010171 animal model Methods 0.000 description 1
• 239000003242 anti bacterial agent Substances 0.000 description 1
• 230000001772 anti-angiogenic effect Effects 0.000 description 1
• 230000000118 anti-neoplastic effect Effects 0.000 description 1
• 230000001028 anti-proliverative effect Effects 0.000 description 1
• 229940088710 antibiotic agent Drugs 0.000 description 1
• 210000000436 anus Anatomy 0.000 description 1
• 230000001640 apoptogenic effect Effects 0.000 description 1
• 238000003782 apoptosis assay Methods 0.000 description 1
• 239000007900 aqueous suspension Substances 0.000 description 1
• 210000001367 artery Anatomy 0.000 description 1
• 210000001188 articular cartilage Anatomy 0.000 description 1
• 125000005129 aryl carbonyl group Chemical group 0.000 description 1
• 235000010323 ascorbic acid Nutrition 0.000 description 1
• 239000011668 ascorbic acid Substances 0.000 description 1
• 229960005070 ascorbic acid Drugs 0.000 description 1
• 230000003143 atherosclerotic effect Effects 0.000 description 1
• 239000005441 aurora Substances 0.000 description 1
• 239000003719 aurora kinase inhibitor Substances 0.000 description 1
• 210000003403 autonomic nervous system Anatomy 0.000 description 1
• 210000000270 basal cell Anatomy 0.000 description 1
• 108010056708 bcr-abl Fusion Proteins Proteins 0.000 description 1
• 102000004441 bcr-abl Fusion Proteins Human genes 0.000 description 1
• 235000010233 benzoic acid Nutrition 0.000 description 1
• 210000000013 bile duct Anatomy 0.000 description 1
• 239000011230 binding agent Substances 0.000 description 1
• 150000001607 bioavailable molecules Chemical class 0.000 description 1
• 238000010256 biochemical assay Methods 0.000 description 1
• 238000010876 biochemical test Methods 0.000 description 1
• 230000033228 biological regulation Effects 0.000 description 1
• 238000001574 biopsy Methods 0.000 description 1
• 125000004057 biotinyl group Chemical class [H]N1C(=O)N([H])[C@]2([H])[C@@]([H])(SC([H])([H])[C@]12[H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 description 1
• 210000003969 blast cell Anatomy 0.000 description 1
• 230000036765 blood level Effects 0.000 description 1
• 230000037396 body weight Effects 0.000 description 1
• 210000000988 bone and bone Anatomy 0.000 description 1
• 210000003557 bones of lower extremity Anatomy 0.000 description 1
• 210000004556 brain Anatomy 0.000 description 1
• 210000000133 brain stem Anatomy 0.000 description 1
• 210000000621 bronchi Anatomy 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
• 230000009702 cancer cell proliferation Effects 0.000 description 1
• 230000000711 cancerogenic effect Effects 0.000 description 1
• 239000007894 caplet Substances 0.000 description 1
• 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
• 231100000315 carcinogenic Toxicity 0.000 description 1
• 210000000845 cartilage Anatomy 0.000 description 1
• 230000003197 catalytic effect Effects 0.000 description 1
• 238000004113 cell culture Methods 0.000 description 1
• 230000025084 cell cycle arrest Effects 0.000 description 1
• 230000009087 cell motility Effects 0.000 description 1
• 210000003855 cell nucleus Anatomy 0.000 description 1
• 239000006285 cell suspension Substances 0.000 description 1
• 231100000147 cell transformation assay Toxicity 0.000 description 1
• 238000003570 cell viability assay Methods 0.000 description 1
• 230000001413 cellular effect Effects 0.000 description 1
• 230000033077 cellular process Effects 0.000 description 1
• 239000001913 cellulose Substances 0.000 description 1
• 229920002678 cellulose Polymers 0.000 description 1
• 235000010980 cellulose Nutrition 0.000 description 1
• 238000002512 chemotherapy Methods 0.000 description 1
• 230000002759 chromosomal effect Effects 0.000 description 1
• 201000010902 chronic myelomonocytic leukemia Diseases 0.000 description 1
• 235000015165 citric acid Nutrition 0.000 description 1
• 239000011248 coating agent Substances 0.000 description 1
• 238000000576 coating method Methods 0.000 description 1
• 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
• 239000003086 colorant Substances 0.000 description 1
• 238000011284 combination treatment Methods 0.000 description 1
• 230000002301 combined effect Effects 0.000 description 1
• 230000002860 competitive effect Effects 0.000 description 1
• 239000002131 composite material Substances 0.000 description 1
• 238000011970 concomitant therapy Methods 0.000 description 1
• 239000003636 conditioned culture medium Substances 0.000 description 1
• 210000002808 connective tissue Anatomy 0.000 description 1
• 230000006552 constitutive activation Effects 0.000 description 1
• 150000004696 coordination complex Chemical class 0.000 description 1
• 210000003792 cranial nerve Anatomy 0.000 description 1
• 239000002577 cryoprotective agent Substances 0.000 description 1
• 238000002425 crystallisation Methods 0.000 description 1
• 230000008025 crystallization Effects 0.000 description 1
• 230000001186 cumulative effect Effects 0.000 description 1
• 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 1
• 125000004122 cyclic group Chemical group 0.000 description 1
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
• 230000009089 cytolysis Effects 0.000 description 1
• 239000000824 cytostatic agent Substances 0.000 description 1
• 230000001085 cytostatic effect Effects 0.000 description 1
• 230000006378 damage Effects 0.000 description 1
• 230000034994 death Effects 0.000 description 1
• 230000017858 demethylation Effects 0.000 description 1
• 238000010520 demethylation reaction Methods 0.000 description 1
• 238000013461 design Methods 0.000 description 1
• 230000037213 diet Effects 0.000 description 1
• 235000005911 diet Nutrition 0.000 description 1
• 238000009792 diffusion process Methods 0.000 description 1
• 210000002249 digestive system Anatomy 0.000 description 1
• 239000003085 diluting agent Substances 0.000 description 1
• 230000006806 disease prevention Effects 0.000 description 1
• 230000007783 downstream signaling Effects 0.000 description 1
• 238000001647 drug administration Methods 0.000 description 1
• 239000003937 drug carrier Substances 0.000 description 1
• 230000009977 dual effect Effects 0.000 description 1
• 210000000959 ear middle Anatomy 0.000 description 1
• 230000002900 effect on cell Effects 0.000 description 1
• 238000001962 electrophoresis Methods 0.000 description 1
• 239000000839 emulsion Substances 0.000 description 1
• 238000005538 encapsulation Methods 0.000 description 1
• 230000002124 endocrine Effects 0.000 description 1
• 210000000750 endocrine system Anatomy 0.000 description 1
• 210000004696 endometrium Anatomy 0.000 description 1
• 238000006345 epimerization reaction Methods 0.000 description 1
• 201000004101 esophageal cancer Diseases 0.000 description 1
• 210000003238 esophagus Anatomy 0.000 description 1
• 230000029142 excretion Effects 0.000 description 1
• 210000001508 eye Anatomy 0.000 description 1
• 201000000497 familial melanoma Diseases 0.000 description 1
• 206010016256 fatigue Diseases 0.000 description 1
• 210000001752 female genitalia Anatomy 0.000 description 1
• 238000000855 fermentation Methods 0.000 description 1
• 230000004151 fermentation Effects 0.000 description 1
• 101150016624 fgfr1 gene Proteins 0.000 description 1
• 101150051367 fgfr1op2 gene Proteins 0.000 description 1
• 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 description 1
• 238000001914 filtration Methods 0.000 description 1
• 238000002376 fluorescence recovery after photobleaching Methods 0.000 description 1
• 230000003325 follicular Effects 0.000 description 1
• 239000012737 fresh medium Substances 0.000 description 1
• 230000002496 gastric effect Effects 0.000 description 1
• 210000001035 gastrointestinal tract Anatomy 0.000 description 1
• 239000000499 gel Substances 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
• 239000007897 gelcap Substances 0.000 description 1
• 230000004077 genetic alteration Effects 0.000 description 1
• 231100000118 genetic alteration Toxicity 0.000 description 1
• 238000003205 genotyping method Methods 0.000 description 1
• 210000004195 gingiva Anatomy 0.000 description 1
• 210000003714 granulocyte Anatomy 0.000 description 1
• 229940093915 gynecological organic acid Drugs 0.000 description 1
• 230000036541 health Effects 0.000 description 1
• 230000003862 health status Effects 0.000 description 1
• 230000004217 heart function Effects 0.000 description 1
• 230000011132 hemopoiesis Effects 0.000 description 1
• 125000000623 heterocyclic group Chemical group 0.000 description 1
• 210000005260 human cell Anatomy 0.000 description 1
• 150000007857 hydrazones Chemical class 0.000 description 1
• 230000002209 hydrophobic effect Effects 0.000 description 1
• 210000003026 hypopharynx Anatomy 0.000 description 1
• 208000025095 immunoproliferative disease Diseases 0.000 description 1
• 230000001506 immunosuppresive effect Effects 0.000 description 1
• 229960003444 immunosuppressant agent Drugs 0.000 description 1
• 230000001861 immunosuppressant effect Effects 0.000 description 1
• 239000003018 immunosuppressive agent Substances 0.000 description 1
• 238000002513 implantation Methods 0.000 description 1
• 238000010874 in vitro model Methods 0.000 description 1
• 239000005414 inactive ingredient Substances 0.000 description 1
• 208000015181 infectious disease Diseases 0.000 description 1
• 230000008595 infiltration Effects 0.000 description 1
• 238000001764 infiltration Methods 0.000 description 1
• 239000004615 ingredient Substances 0.000 description 1
• 208000014674 injury Diseases 0.000 description 1
• 229940125396 insulin Drugs 0.000 description 1
• 230000003993 interaction Effects 0.000 description 1
• 238000001361 intraarterial administration Methods 0.000 description 1
• 210000003228 intrahepatic bile duct Anatomy 0.000 description 1
• 238000007912 intraperitoneal administration Methods 0.000 description 1
• 238000010253 intravenous injection Methods 0.000 description 1
• JORABGDXCIBAFL-UHFFFAOYSA-M iodonitrotetrazolium chloride Chemical compound [Cl-].C1=CC([N+](=O)[O-])=CC=C1N1[N+](C=2C=CC(I)=CC=2)=NC(C=2C=CC=CC=2)=N1 JORABGDXCIBAFL-UHFFFAOYSA-M 0.000 description 1
• 229910052742 iron Inorganic materials 0.000 description 1
• 230000001788 irregular Effects 0.000 description 1
• YWXYYJSYQOXTPL-SLPGGIOYSA-N isosorbide mononitrate Chemical compound [O-][N+](=O)O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-SLPGGIOYSA-N 0.000 description 1
• 125000000468 ketone group Chemical group 0.000 description 1
• 230000003907 kidney function Effects 0.000 description 1
• 210000000244 kidney pelvis Anatomy 0.000 description 1
• 150000003951 lactams Chemical class 0.000 description 1
• 239000004310 lactic acid Substances 0.000 description 1
• 235000014655 lactic acid Nutrition 0.000 description 1
• 230000000670 limiting effect Effects 0.000 description 1
• 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
• 235000019421 lipase Nutrition 0.000 description 1
• 239000007788 liquid Substances 0.000 description 1
• 201000007270 liver cancer Diseases 0.000 description 1
• 230000003908 liver function Effects 0.000 description 1
• 208000014018 liver neoplasm Diseases 0.000 description 1
• 238000001325 log-rank test Methods 0.000 description 1
• 208000037841 lung tumor Diseases 0.000 description 1
• 210000002751 lymph Anatomy 0.000 description 1
• 210000004698 lymphocyte Anatomy 0.000 description 1
• 208000019420 lymphoid neoplasm Diseases 0.000 description 1
• 210000002540 macrophage Anatomy 0.000 description 1
• 210000000260 male genitalia Anatomy 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
• 239000001630 malic acid Substances 0.000 description 1
• 235000011090 malic acid Nutrition 0.000 description 1
• 230000036210 malignancy Effects 0.000 description 1
• 239000003550 marker Substances 0.000 description 1
• 108010082117 matrigel Proteins 0.000 description 1
• 230000007246 mechanism Effects 0.000 description 1
• 210000002418 meninge Anatomy 0.000 description 1
• 230000004060 metabolic process Effects 0.000 description 1
• 229910052751 metal Inorganic materials 0.000 description 1
• 239000002184 metal Substances 0.000 description 1
• 230000009401 metastasis Effects 0.000 description 1
• 208000037819 metastatic cancer Diseases 0.000 description 1
• 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
• 229940098779 methanesulfonic acid Drugs 0.000 description 1
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
• 150000004702 methyl esters Chemical group 0.000 description 1
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
• 229940016286 microcrystalline cellulose Drugs 0.000 description 1
• 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
• 239000008108 microcrystalline cellulose Substances 0.000 description 1
• 235000013336 milk Nutrition 0.000 description 1
• 239000008267 milk Substances 0.000 description 1
• 210000004080 milk Anatomy 0.000 description 1
• 230000003278 mimic effect Effects 0.000 description 1
• 150000007522 mineralic acids Chemical class 0.000 description 1
• 231100000324 minimal toxicity Toxicity 0.000 description 1
• 238000011242 molecular targeted therapy Methods 0.000 description 1
• 238000012544 monitoring process Methods 0.000 description 1
• 201000006894 monocytic leukemia Diseases 0.000 description 1
• 239000012452 mother liquor Substances 0.000 description 1
• 229940043363 multi-kinase inhibitor Drugs 0.000 description 1
• 229940124303 multikinase inhibitor Drugs 0.000 description 1
• 210000003205 muscle Anatomy 0.000 description 1
• 231100000150 mutagenicity / genotoxicity testing Toxicity 0.000 description 1
• 201000005962 mycosis fungoides Diseases 0.000 description 1
• 210000001167 myeloblast Anatomy 0.000 description 1
• 208000016586 myelodysplastic syndrome with excess blasts Diseases 0.000 description 1
• 206010028537 myelofibrosis Diseases 0.000 description 1
• 208000016956 myeloid neoplasm associated with FGFR1 rearrangement Diseases 0.000 description 1
• PCOBUQBNVYZTBU-UHFFFAOYSA-N myricetin Natural products OC1=C(O)C(O)=CC(C=2OC3=CC(O)=C(O)C(O)=C3C(=O)C=2)=C1 PCOBUQBNVYZTBU-UHFFFAOYSA-N 0.000 description 1
• 235000007743 myricetin Nutrition 0.000 description 1
• 229940116852 myricetin Drugs 0.000 description 1
• WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
• SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
• 210000003928 nasal cavity Anatomy 0.000 description 1
• 210000001989 nasopharynx Anatomy 0.000 description 1
• 230000008693 nausea Effects 0.000 description 1
• 230000014399 negative regulation of angiogenesis Effects 0.000 description 1
• 230000017066 negative regulation of growth Effects 0.000 description 1
• 210000005036 nerve Anatomy 0.000 description 1
• 210000000653 nervous system Anatomy 0.000 description 1
• 206010061311 nervous system neoplasm Diseases 0.000 description 1
• 231100000252 nontoxic Toxicity 0.000 description 1
• 230000003000 nontoxic effect Effects 0.000 description 1
• 210000003924 normoblast Anatomy 0.000 description 1
• 230000035764 nutrition Effects 0.000 description 1
• 235000016709 nutrition Nutrition 0.000 description 1
• 231100000590 oncogenic Toxicity 0.000 description 1
• 230000002246 oncogenic effect Effects 0.000 description 1
• 238000005457 optimization Methods 0.000 description 1
• 150000007524 organic acids Chemical class 0.000 description 1
• 235000005985 organic acids Nutrition 0.000 description 1
• 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
• 210000004798 organs belonging to the digestive system Anatomy 0.000 description 1
• 210000003300 oropharynx Anatomy 0.000 description 1
• 210000003254 palate Anatomy 0.000 description 1
• 210000002741 palatine tonsil Anatomy 0.000 description 1
• WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 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
• 210000003681 parotid gland Anatomy 0.000 description 1
• 230000036961 partial effect Effects 0.000 description 1
• 239000002245 particle Substances 0.000 description 1
• 239000008188 pellet Substances 0.000 description 1
• 229940056360 penicillin g Drugs 0.000 description 1
• 210000003899 penis Anatomy 0.000 description 1
• 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
• 230000002093 peripheral effect Effects 0.000 description 1
• 210000004303 peritoneum Anatomy 0.000 description 1
• 229940124531 pharmaceutical excipient Drugs 0.000 description 1
• 238000002733 pharmacodynamic assay Methods 0.000 description 1
• JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 1
• 108091005981 phosphorylated proteins Proteins 0.000 description 1
• DCWXELXMIBXGTH-UHFFFAOYSA-N phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 description 1
• 239000006187 pill Substances 0.000 description 1
• HXEACLLIILLPRG-UHFFFAOYSA-N pipecolic acid Chemical group OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 description 1
• 210000002826 placenta Anatomy 0.000 description 1
• 208000010626 plasma cell neoplasm Diseases 0.000 description 1
• 210000004224 pleura Anatomy 0.000 description 1
• 229920000573 polyethylene Polymers 0.000 description 1
• 239000003755 preservative agent Substances 0.000 description 1
• 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
• 208000029340 primitive neuroectodermal tumor Diseases 0.000 description 1
• 230000008569 process Effects 0.000 description 1
• 108090000765 processed proteins & peptides Proteins 0.000 description 1
• 239000000651 prodrug Substances 0.000 description 1
• 229940002612 prodrug Drugs 0.000 description 1
• 208000037821 progressive disease Diseases 0.000 description 1
• 230000002062 proliferating effect Effects 0.000 description 1
• 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
• 230000000069 prophylactic effect Effects 0.000 description 1
• 230000009822 protein phosphorylation Effects 0.000 description 1
• 238000001243 protein synthesis Methods 0.000 description 1
• 108020000494 protein-tyrosine phosphatase Proteins 0.000 description 1
• 230000002797 proteolythic effect Effects 0.000 description 1
• 238000000746 purification Methods 0.000 description 1
• 238000011002 quantification Methods 0.000 description 1
• 229940099538 rapamune Drugs 0.000 description 1
• 230000007420 reactivation Effects 0.000 description 1
• 206010038038 rectal cancer Diseases 0.000 description 1
• 210000000664 rectum Anatomy 0.000 description 1
• 201000001275 rectum cancer Diseases 0.000 description 1
• 238000007634 remodeling Methods 0.000 description 1
• 230000010076 replication Effects 0.000 description 1
• 210000004994 reproductive system Anatomy 0.000 description 1
• 239000011347 resin Substances 0.000 description 1
• 229920005989 resin Polymers 0.000 description 1
• 230000000241 respiratory effect Effects 0.000 description 1
• 230000004043 responsiveness Effects 0.000 description 1
• 210000001525 retina Anatomy 0.000 description 1
• 210000000574 retroperitoneal space Anatomy 0.000 description 1
• 229960004889 salicylic acid Drugs 0.000 description 1
• 210000003079 salivary gland Anatomy 0.000 description 1
• 238000009118 salvage therapy Methods 0.000 description 1
• 238000005070 sampling Methods 0.000 description 1
• 238000012163 sequencing technique Methods 0.000 description 1
• 230000001568 sexual effect Effects 0.000 description 1
• 238000007873 sieving Methods 0.000 description 1
• 229910052710 silicon Inorganic materials 0.000 description 1
• 239000010703 silicon Substances 0.000 description 1
• 238000001542 size-exclusion chromatography Methods 0.000 description 1
• 208000020352 skin basal cell carcinoma Diseases 0.000 description 1
• 201000008261 skin carcinoma Diseases 0.000 description 1
• 201000010106 skin squamous cell carcinoma Diseases 0.000 description 1
• 208000000587 small cell lung carcinoma Diseases 0.000 description 1
• 210000000813 small intestine Anatomy 0.000 description 1
• 201000002314 small intestine cancer Diseases 0.000 description 1
• 239000001632 sodium acetate Substances 0.000 description 1
• 235000017281 sodium acetate Nutrition 0.000 description 1
• 238000001228 spectrum Methods 0.000 description 1
• 210000000278 spinal cord Anatomy 0.000 description 1
• 230000002269 spontaneous effect Effects 0.000 description 1
• 239000007921 spray Substances 0.000 description 1
• 239000003381 stabilizer Substances 0.000 description 1
• 238000010186 staining Methods 0.000 description 1
• 238000010561 standard procedure Methods 0.000 description 1
• 238000011301 standard therapy Methods 0.000 description 1
• 150000003871 sulfonates Chemical class 0.000 description 1
• 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
• 239000007916 tablet composition Substances 0.000 description 1
• 230000008685 targeting Effects 0.000 description 1
• 235000002906 tartaric acid Nutrition 0.000 description 1
• 239000011975 tartaric acid Substances 0.000 description 1
• 229960001367 tartaric acid Drugs 0.000 description 1
• 229940124597 therapeutic agent Drugs 0.000 description 1
• 231100001274 therapeutic index Toxicity 0.000 description 1
• 206010043554 thrombocytopenia Diseases 0.000 description 1
• 208000013076 thyroid tumor Diseases 0.000 description 1
• 230000036962 time dependent Effects 0.000 description 1
• 239000004408 titanium dioxide Substances 0.000 description 1
• 231100000419 toxicity Toxicity 0.000 description 1
• 230000001988 toxicity Effects 0.000 description 1
• 210000003437 trachea Anatomy 0.000 description 1
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
• 238000013518 transcription Methods 0.000 description 1
• 230000035897 transcription Effects 0.000 description 1
• 230000001052 transient effect Effects 0.000 description 1
• 230000007704 transition Effects 0.000 description 1
• 230000014616 translation Effects 0.000 description 1
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
• 230000010304 tumor cell viability Effects 0.000 description 1
• 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
• 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
• 150000003668 tyrosines Chemical class 0.000 description 1
• 210000000626 ureter Anatomy 0.000 description 1
• 230000002485 urinary effect Effects 0.000 description 1
• 206010046766 uterine cancer Diseases 0.000 description 1
• 208000024719 uterine cervix neoplasm Diseases 0.000 description 1
• 210000001215 vagina Anatomy 0.000 description 1
• 238000011179 visual inspection Methods 0.000 description 1
• 210000003905 vulva Anatomy 0.000 description 1
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
• 238000012447 xenograft mouse model Methods 0.000 description 1