ES2367666T3 - Derivados de [4,5']bipirimidinil-6,4'-diamina como inhibidores de proteína quinasa. - Google Patents

Info

Publication number

ES2367666T3

ES2367666T3 ES07812739T ES07812739T ES2367666T3 ES 2367666 T3 ES2367666 T3 ES 2367666T3 ES 07812739 T ES07812739 T ES 07812739T ES 07812739 T ES07812739 T ES 07812739T ES 2367666 T3 ES2367666 T3 ES 2367666T3

Authority

ES

Spain

Prior art keywords

bipyrimidinyl

pyridin

dimethoxy

phenyl

ylamino

Prior art date

2006-07-12

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Active

Links

• Espacenet
• Global Dossier
• Discuss

• 108090000623 proteins and genes Proteins 0.000 title description 10
• 239000003112 inhibitor Substances 0.000 title description 9
• 102000004169 proteins and genes Human genes 0.000 title description 5
• -1 piperidino, piperazino Chemical group 0.000 claims abstract description 319
• 150000001875 compounds Chemical class 0.000 claims abstract description 229
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 70
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 69
• 239000001257 hydrogen Substances 0.000 claims abstract description 69
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 62
• 125000002950 monocyclic group Chemical group 0.000 claims abstract description 36
• 150000003839 salts Chemical class 0.000 claims abstract description 36
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 30
• 229910052799 carbon Inorganic materials 0.000 claims abstract description 27
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 27
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 27
• 229920006395 saturated elastomer Polymers 0.000 claims abstract description 23
• 125000002947 alkylene group Chemical group 0.000 claims abstract description 18
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 16
• 150000001204 N-oxides Chemical class 0.000 claims abstract description 16
• 125000002619 bicyclic group Chemical group 0.000 claims abstract description 15
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 9
• 239000012453 solvate Substances 0.000 claims abstract description 9
• 229940002612 prodrug Drugs 0.000 claims abstract description 8
• 239000000651 prodrug Substances 0.000 claims abstract description 8
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 7
• 125000001424 substituent group Chemical group 0.000 claims abstract description 7
• 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims abstract description 6
• 125000000041 C6-C10 aryl group Chemical group 0.000 claims abstract description 6
• 125000002887 hydroxy group Chemical class [H]O* 0.000 claims abstract description 6
• 150000004677 hydrates Chemical class 0.000 claims abstract description 5
• 125000003118 aryl group Chemical group 0.000 claims abstract description 3
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 44
• 230000000694 effects Effects 0.000 claims description 42
• 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 claims description 39
• 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 claims description 39
• 201000010099 disease Diseases 0.000 claims description 33
• 206010028980 Neoplasm Diseases 0.000 claims description 31
• 238000011282 treatment Methods 0.000 claims description 26
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
• 239000002253 acid Substances 0.000 claims description 20
• 230000035755 proliferation Effects 0.000 claims description 13
• 239000003814 drug Substances 0.000 claims description 12
• 229910052731 fluorine Inorganic materials 0.000 claims description 10
• 239000011737 fluorine Chemical group 0.000 claims description 10
• 125000005843 halogen group Chemical group 0.000 claims description 9
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
• 239000000460 chlorine Chemical group 0.000 claims description 7
• 229910052801 chlorine Inorganic materials 0.000 claims description 7
• 150000004985 diamines Chemical class 0.000 claims description 7
• 208000023275 Autoimmune disease Diseases 0.000 claims description 6
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
• 241001465754 Metazoa Species 0.000 claims description 6
• 230000007170 pathology Effects 0.000 claims description 6
• 210000001744 T-lymphocyte Anatomy 0.000 claims description 5
• 208000027866 inflammatory disease Diseases 0.000 claims description 5
• 238000004519 manufacturing process Methods 0.000 claims description 5
• 230000001404 mediated effect Effects 0.000 claims description 5
• 150000004702 methyl esters Chemical class 0.000 claims description 5
• 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 4
• 206010005003 Bladder cancer Diseases 0.000 claims description 4
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
• 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 4
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
• 229910052794 bromium Inorganic materials 0.000 claims description 4
• 125000004076 pyridyl group Chemical group 0.000 claims description 4
• 201000005112 urinary bladder cancer Diseases 0.000 claims description 4
• ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 3
• 125000000217 alkyl group Chemical group 0.000 claims description 3
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
• 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
• DEQWECAWVNDIHY-UHFFFAOYSA-N n-(2,6-dichloro-3,5-dimethoxyphenyl)-3-[6-[[5-(morpholin-4-ylmethyl)pyridin-2-yl]amino]pyrimidin-4-yl]pyrazin-2-amine Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=NC=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCOCC4)=CC=3)C=2)=C1Cl DEQWECAWVNDIHY-UHFFFAOYSA-N 0.000 claims description 3
• TYOCSGNRWAHCPK-UHFFFAOYSA-N 1-[3-[[6-[4-(2,6-dichloro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]phenyl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3C=C(C=CC=3)C(C)O)C=2)=C1Cl TYOCSGNRWAHCPK-UHFFFAOYSA-N 0.000 claims description 2
• WIGBPFMLSVEBSH-UHFFFAOYSA-N 1-[3-[[6-[4-(2,6-difluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]phenyl]ethanol Chemical compound COC1=CC(OC)=C(F)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3C=C(C=CC=3)C(C)O)C=2)=C1F WIGBPFMLSVEBSH-UHFFFAOYSA-N 0.000 claims description 2
• KDHDEIZNVKDEEH-UHFFFAOYSA-N 1-[4-[6-[[6-[3-(2,6-dichloro-3,5-dimethoxyanilino)pyrazin-2-yl]pyrimidin-4-yl]amino]pyridin-3-yl]piperazin-1-yl]-2-hydroxyethanone Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=NC=CN=2)C=2N=CN=C(NC=3N=CC(=CC=3)N3CCN(CC3)C(=O)CO)C=2)=C1Cl KDHDEIZNVKDEEH-UHFFFAOYSA-N 0.000 claims description 2
• NMMBKQUZGJYFKU-UHFFFAOYSA-N 1-[4-[[6-[[6-[4-(2,6-dichloro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]ethanone Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CC4)C(C)=O)=CC=3)C=2)=C1Cl NMMBKQUZGJYFKU-UHFFFAOYSA-N 0.000 claims description 2
• LFWDKYXONJPXLV-UHFFFAOYSA-N 1-[6-[[6-[4-(2,6-dichloro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(=CC=3)C(C)O)C=2)=C1Cl LFWDKYXONJPXLV-UHFFFAOYSA-N 0.000 claims description 2
• STNPCJBTHDGVDG-UHFFFAOYSA-N 1-[6-[[6-[4-(2-chloro-3,5-dimethoxy-6-methylanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(=CC=3)C(C)O)C=2)=C1C STNPCJBTHDGVDG-UHFFFAOYSA-N 0.000 claims description 2
• OQKZUTMDCSLCLS-UHFFFAOYSA-N 1-[6-[[6-[4-(2-fluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]ethanol Chemical compound COC1=CC(OC)=CC(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(=CC=3)C(C)O)C=2)=C1F OQKZUTMDCSLCLS-UHFFFAOYSA-N 0.000 claims description 2
• HBJDUPZNFBWSNF-UHFFFAOYSA-N 2-[4-[[6-[[6-[4-(2,6-difluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]ethanol Chemical compound COC1=CC(OC)=C(F)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CCO)CC4)=CC=3)C=2)=C1F HBJDUPZNFBWSNF-UHFFFAOYSA-N 0.000 claims description 2
• XUPGEWMUHRNEHO-UHFFFAOYSA-N 2-[4-[[6-[[6-[4-(2-chloro-3,5-dimethoxy-6-methylanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CCO)CC4)=CC=3)C=2)=C1C XUPGEWMUHRNEHO-UHFFFAOYSA-N 0.000 claims description 2
• 125000000872 2-diethylaminoethoxy group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 claims description 2
• YUCPGZSYMDFVJE-UHFFFAOYSA-N 3-(6-aminopyrimidin-4-yl)-n-(2,6-dichlorophenyl)pyrazin-2-amine Chemical compound C1=NC(N)=CC(C=2C(=NC=CN=2)NC=2C(=CC=CC=2Cl)Cl)=N1 YUCPGZSYMDFVJE-UHFFFAOYSA-N 0.000 claims description 2
• FHVWPPCTAIQSHC-UHFFFAOYSA-N 3-(6-aminopyrimidin-4-yl)-n-(2,6-difluoro-3-methoxyphenyl)pyrazin-2-amine Chemical compound COC1=CC=C(F)C(NC=2C(=NC=CN=2)C=2N=CN=C(N)C=2)=C1F FHVWPPCTAIQSHC-UHFFFAOYSA-N 0.000 claims description 2
• 239000005711 Benzoic acid Substances 0.000 claims description 2
• 150000001408 amides Chemical class 0.000 claims description 2
• 230000008468 bone growth Effects 0.000 claims description 2
• 210000001612 chondrocyte Anatomy 0.000 claims description 2
• QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 claims description 2
• CXTQRJIXPYUUSY-UHFFFAOYSA-N n-(2,6-dichlorophenyl)-3-[6-[4-[2-(diethylamino)ethoxy]anilino]pyrimidin-4-yl]pyrazin-2-amine Chemical compound C1=CC(OCCN(CC)CC)=CC=C1NC1=CC(C=2C(=NC=CN=2)NC=2C(=CC=CC=2Cl)Cl)=NC=N1 CXTQRJIXPYUUSY-UHFFFAOYSA-N 0.000 claims description 2
• RWKOJOJGEWDVNF-UHFFFAOYSA-N n-(2,6-dichlorophenyl)-3-[6-[[5-(2-morpholin-4-ylethyl)pyridin-2-yl]amino]pyrimidin-4-yl]pyrazin-2-amine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NC=CN=C1C1=CC(NC=2N=CC(CCN3CCOCC3)=CC=2)=NC=N1 RWKOJOJGEWDVNF-UHFFFAOYSA-N 0.000 claims description 2
• CQYCMUYFDNMOFE-UHFFFAOYSA-N n-(2,6-dichlorophenyl)-3-[6-[[5-(morpholin-4-ylmethyl)pyridin-2-yl]amino]pyrimidin-4-yl]pyrazin-2-amine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NC=CN=C1C1=CC(NC=2N=CC(CN3CCOCC3)=CC=2)=NC=N1 CQYCMUYFDNMOFE-UHFFFAOYSA-N 0.000 claims description 2
• YKLFRTKTQNBSNA-UHFFFAOYSA-N n-(2,6-difluoro-3-methoxyphenyl)-3-[6-[[4-(morpholin-4-ylmethyl)pyridin-2-yl]amino]pyrimidin-4-yl]pyrazin-2-amine Chemical compound COC1=CC=C(F)C(NC=2C(=NC=CN=2)C=2N=CN=C(NC=3N=CC=C(CN4CCOCC4)C=3)C=2)=C1F YKLFRTKTQNBSNA-UHFFFAOYSA-N 0.000 claims description 2
• ZQFYTRGAIARKKE-UHFFFAOYSA-N n-(2,6-difluoro-3-methoxyphenyl)-3-[6-[[5-(morpholin-4-ylmethyl)pyridin-2-yl]amino]pyrimidin-4-yl]pyrazin-2-amine Chemical compound COC1=CC=C(F)C(NC=2C(=NC=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCOCC4)=CC=3)C=2)=C1F ZQFYTRGAIARKKE-UHFFFAOYSA-N 0.000 claims description 2
• CDQIWPKYEYLVKR-UHFFFAOYSA-N n-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-3-[6-[[5-(morpholin-4-ylmethyl)pyridin-2-yl]amino]pyrimidin-4-yl]pyrazin-2-amine Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=NC=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCOCC4)=CC=3)C=2)=C1F CDQIWPKYEYLVKR-UHFFFAOYSA-N 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• ZXOGVOGAINUMFX-UHFFFAOYSA-N 1-[3-[[6-[4-(2-chloro-6-fluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]phenyl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3C=C(C=CC=3)C(C)O)C=2)=C1F ZXOGVOGAINUMFX-UHFFFAOYSA-N 0.000 claims 1
• PNCFUDLLXJUXSH-UHFFFAOYSA-N 1-[4-[[6-[[6-[4-(2,6-difluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]ethanone Chemical compound COC1=CC(OC)=C(F)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CC4)C(C)=O)=CC=3)C=2)=C1F PNCFUDLLXJUXSH-UHFFFAOYSA-N 0.000 claims 1
• AYJYBVQKLXRDQJ-UHFFFAOYSA-N 1-[4-[[6-[[6-[4-(2-chloro-6-fluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]-2-hydroxyethanone Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CC4)C(=O)CO)=CC=3)C=2)=C1F AYJYBVQKLXRDQJ-UHFFFAOYSA-N 0.000 claims 1
• WXASKJZNTGILEK-UHFFFAOYSA-N 1-[6-[[6-[4-(2-chloro-6-fluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(=CC=3)C(C)O)C=2)=C1F WXASKJZNTGILEK-UHFFFAOYSA-N 0.000 claims 1
• RMCRWRACPLILML-UHFFFAOYSA-N 2-[4-[6-[[6-[3-(2,6-dichloro-3,5-dimethoxyanilino)pyrazin-2-yl]pyrimidin-4-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=NC=CN=2)C=2N=CN=C(NC=3N=CC(=CC=3)N3CCN(CCO)CC3)C=2)=C1Cl RMCRWRACPLILML-UHFFFAOYSA-N 0.000 claims 1
• MWXFVCCQBSSGDD-UHFFFAOYSA-N 2-[4-[[6-[[6-[4-(2,6-dichloro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CCO)CC4)=CC=3)C=2)=C1Cl MWXFVCCQBSSGDD-UHFFFAOYSA-N 0.000 claims 1
• SWQLRHRBOQUCSW-UHFFFAOYSA-N 2-[4-[[6-[[6-[4-(2-chloro-6-fluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CCO)CC4)=CC=3)C=2)=C1F SWQLRHRBOQUCSW-UHFFFAOYSA-N 0.000 claims 1
• XYIBIKYKRKQRGW-UHFFFAOYSA-N 2-[4-[[6-[[6-[4-(2-fluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]ethanol Chemical compound COC1=CC(OC)=CC(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CCO)CC4)=CC=3)C=2)=C1F XYIBIKYKRKQRGW-UHFFFAOYSA-N 0.000 claims 1
• ZZGSXDHMSPQHBF-UHFFFAOYSA-N 4-[[6-[[6-[4-(2,6-dichloro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazine-1-carboxylic acid Chemical compound ClC1=C(C(=C(C=C1OC)OC)Cl)NC1=NC=NC=C1C1=NC=NC(=C1)NC1=CC=C(C=N1)CN1CCN(CC1)C(=O)O ZZGSXDHMSPQHBF-UHFFFAOYSA-N 0.000 claims 1
• LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims 1
• 108091008648 NR7C Proteins 0.000 claims 1
• KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 1
• 239000004202 carbamide Substances 0.000 claims 1
• 125000001153 fluoro group Chemical group F* 0.000 claims 1
• 230000002757 inflammatory effect Effects 0.000 claims 1
• IMLBLNTWKDEHCS-UHFFFAOYSA-N n-(2,6-dichloro-3,5-dimethoxyphenyl)-3-[6-[[4-(2-morpholin-4-ylethyl)pyridin-2-yl]amino]pyrimidin-4-yl]pyrazin-2-amine Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=NC=CN=2)C=2N=CN=C(NC=3N=CC=C(CCN4CCOCC4)C=3)C=2)=C1Cl IMLBLNTWKDEHCS-UHFFFAOYSA-N 0.000 claims 1
• XTBHWTYTNGOVJE-UHFFFAOYSA-N n-(2,6-dichlorophenyl)-3-[6-[4-(4-ethylpiperazin-1-yl)anilino]pyrimidin-4-yl]pyrazin-2-amine Chemical compound C1CN(CC)CCN1C(C=C1)=CC=C1NC1=CC(C=2C(=NC=CN=2)NC=2C(=CC=CC=2Cl)Cl)=NC=N1 XTBHWTYTNGOVJE-UHFFFAOYSA-N 0.000 claims 1
• 125000001475 halogen functional group Chemical group 0.000 abstract 2
• 201000006417 multiple sclerosis Diseases 0.000 description 153
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 94
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 79
• 210000004027 cell Anatomy 0.000 description 71
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 66
• 238000005160 1H NMR spectroscopy Methods 0.000 description 61
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 59
• 108091000080 Phosphotransferase Proteins 0.000 description 43
• 102000020233 phosphotransferase Human genes 0.000 description 43
• 238000006243 chemical reaction Methods 0.000 description 42
• 239000000203 mixture Substances 0.000 description 32
• 239000000243 solution Substances 0.000 description 32
• 238000000034 method Methods 0.000 description 31
• 235000019439 ethyl acetate Nutrition 0.000 description 30
• 239000007787 solid Substances 0.000 description 30
• 238000005481 NMR spectroscopy Methods 0.000 description 29
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
• WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 23
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 23
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 23
• 239000000725 suspension Substances 0.000 description 23
• 239000002904 solvent Substances 0.000 description 22
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
• 238000003756 stirring Methods 0.000 description 20
• 230000001413 cellular effect Effects 0.000 description 18
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
• 230000005764 inhibitory process Effects 0.000 description 17
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
• 230000014509 gene expression Effects 0.000 description 16
• 230000035772 mutation Effects 0.000 description 16
• 239000011541 reaction mixture Substances 0.000 description 16
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
• 239000012267 brine Substances 0.000 description 14
• 239000000047 product Substances 0.000 description 14
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
• 239000003795 chemical substances by application Substances 0.000 description 13
• 238000001914 filtration Methods 0.000 description 13
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 12
• 101150058160 Lyn gene Proteins 0.000 description 12
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
• 238000003818 flash chromatography Methods 0.000 description 12
• OKOWOYJLYGCVSF-UHFFFAOYSA-N n-(3,5-dimethoxyphenyl)acetamide Chemical compound COC1=CC(NC(C)=O)=CC(OC)=C1 OKOWOYJLYGCVSF-UHFFFAOYSA-N 0.000 description 12
• 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 11
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
• 101100381978 Mus musculus Braf gene Proteins 0.000 description 11
• 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 11
• 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 11
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
• 208000035475 disorder Diseases 0.000 description 11
• 239000000758 substrate Substances 0.000 description 11
• 239000000872 buffer Substances 0.000 description 10
• 201000011510 cancer Diseases 0.000 description 10
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
• LCQFHEIDCMPNAN-UHFFFAOYSA-N 2,6-dichloro-3,5-dimethoxyaniline Chemical compound COC1=CC(OC)=C(Cl)C(N)=C1Cl LCQFHEIDCMPNAN-UHFFFAOYSA-N 0.000 description 9
• 101150028321 Lck gene Proteins 0.000 description 9
• 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 9
• 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 9
• 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 9
• 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 9
• 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 9
• 230000004913 activation Effects 0.000 description 9
• 239000012043 crude product Substances 0.000 description 9
• 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 description 9
• 102000005962 receptors Human genes 0.000 description 9
• 108020003175 receptors Proteins 0.000 description 9
• 230000011664 signaling Effects 0.000 description 9
• 239000000741 silica gel Substances 0.000 description 9
• 229910002027 silica gel Inorganic materials 0.000 description 9
• 210000003556 vascular endothelial cell Anatomy 0.000 description 9
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
• 108700020796 Oncogene Proteins 0.000 description 8
• 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 8
• 230000002159 abnormal effect Effects 0.000 description 8
• 238000004458 analytical method Methods 0.000 description 8
• 238000002360 preparation method Methods 0.000 description 8
• 239000007858 starting material Substances 0.000 description 8
• 238000012360 testing method Methods 0.000 description 8
• VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
• CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 8
• QBLKLNIQCVBMRS-UHFFFAOYSA-N 3-(6-aminopyrimidin-4-yl)-n-(2,6-dichloro-3,5-dimethoxyphenyl)pyrazin-2-amine Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=NC=CN=2)C=2N=CN=C(N)C=2)=C1Cl QBLKLNIQCVBMRS-UHFFFAOYSA-N 0.000 description 7
• 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 7
• 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 7
• 239000004480 active ingredient Substances 0.000 description 7
• 229940079593 drug Drugs 0.000 description 7
• GAWCNXFUPQOIJU-UHFFFAOYSA-N n-(2,6-dichloro-3,5-dimethoxyphenyl)acetamide Chemical compound COC1=CC(OC)=C(Cl)C(NC(C)=O)=C1Cl GAWCNXFUPQOIJU-UHFFFAOYSA-N 0.000 description 7
• 239000012044 organic layer Substances 0.000 description 7
• 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 7
• 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 7
• 230000008569 process Effects 0.000 description 7
• 230000002062 proliferating effect Effects 0.000 description 7
• 206010039073 rheumatoid arthritis Diseases 0.000 description 7
• 210000001519 tissue Anatomy 0.000 description 7
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 6
• BMQSAIGMUNXTKZ-UHFFFAOYSA-N 4-chloro-6-methylsulfanylpyrimidine Chemical compound CSC1=CC(Cl)=NC=N1 BMQSAIGMUNXTKZ-UHFFFAOYSA-N 0.000 description 6
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
• 108090000695 Cytokines Proteins 0.000 description 6
• 102000004127 Cytokines Human genes 0.000 description 6
• 101100481408 Danio rerio tie2 gene Proteins 0.000 description 6
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
• 102000043136 MAP kinase family Human genes 0.000 description 6
• 108091054455 MAP kinase family Proteins 0.000 description 6
• 101100481410 Mus musculus Tek gene Proteins 0.000 description 6
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
• 239000007832 Na2SO4 Substances 0.000 description 6
• 102000001253 Protein Kinase Human genes 0.000 description 6
• 102000001788 Proto-Oncogene Proteins c-raf Human genes 0.000 description 6
• 108010029869 Proto-Oncogene Proteins c-raf Proteins 0.000 description 6
• 108060006706 SRC Proteins 0.000 description 6
• 102000001332 SRC Human genes 0.000 description 6
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
• 230000006907 apoptotic process Effects 0.000 description 6
• 230000015572 biosynthetic process Effects 0.000 description 6
• 239000000706 filtrate Substances 0.000 description 6
• 230000012010 growth Effects 0.000 description 6
• MZJXSHDLLCTIKC-UHFFFAOYSA-N n-(2,6-dichloro-3,5-dimethoxyphenyl)-3-(6-methylsulfanylpyrimidin-4-yl)pyrazin-2-amine Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=NC=CN=2)C=2N=CN=C(SC)C=2)=C1Cl MZJXSHDLLCTIKC-UHFFFAOYSA-N 0.000 description 6
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 6
• 108060006633 protein kinase Proteins 0.000 description 6
• 108091008598 receptor tyrosine kinases Proteins 0.000 description 6
• 102000027426 receptor tyrosine kinases Human genes 0.000 description 6
• 230000001105 regulatory effect Effects 0.000 description 6
• 229910052938 sodium sulfate Inorganic materials 0.000 description 6
• 235000011152 sodium sulphate Nutrition 0.000 description 6
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
• CWOLBACJMBLPNC-UHFFFAOYSA-N 2-chloro-3-(6-methylsulfanylpyrimidin-4-yl)pyrazine Chemical compound C1=NC(SC)=CC(C=2C(=NC=CN=2)Cl)=N1 CWOLBACJMBLPNC-UHFFFAOYSA-N 0.000 description 5
• 206010006187 Breast cancer Diseases 0.000 description 5
• 208000026310 Breast neoplasm Diseases 0.000 description 5
• 101100381481 Caenorhabditis elegans baz-2 gene Proteins 0.000 description 5
• 208000034578 Multiple myelomas Diseases 0.000 description 5
• 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 5
• 206010035226 Plasma cell myeloma Diseases 0.000 description 5
• 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 5
• 101100372762 Rattus norvegicus Flt1 gene Proteins 0.000 description 5
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
• 239000006180 TBST buffer Substances 0.000 description 5
• RYXZOQOZERSHHQ-UHFFFAOYSA-N [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenylphosphane Chemical compound C=1C=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1OC1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RYXZOQOZERSHHQ-UHFFFAOYSA-N 0.000 description 5
• 239000002585 base Substances 0.000 description 5
• 238000000423 cell based assay Methods 0.000 description 5
• 230000006870 function Effects 0.000 description 5
• 201000001441 melanoma Diseases 0.000 description 5
• LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 5
• 108090000765 processed proteins & peptides Proteins 0.000 description 5
• 238000000746 purification Methods 0.000 description 5
• 238000003786 synthesis reaction Methods 0.000 description 5
• SUXITUVUFUOAGT-UHFFFAOYSA-N 2,6-difluoro-3,5-dimethoxyaniline Chemical compound COC1=CC(OC)=C(F)C(N)=C1F SUXITUVUFUOAGT-UHFFFAOYSA-N 0.000 description 4
• 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 4
• 208000031261 Acute myeloid leukaemia Diseases 0.000 description 4
• 201000001320 Atherosclerosis Diseases 0.000 description 4
• 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 4
• 108010024121 Janus Kinases Proteins 0.000 description 4
• 102000015617 Janus Kinases Human genes 0.000 description 4
• 239000005517 L01XE01 - Imatinib Substances 0.000 description 4
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
• 201000004681 Psoriasis Diseases 0.000 description 4
• PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 4
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
• 101150110875 Syk gene Proteins 0.000 description 4
• 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 4
• 150000001412 amines Chemical class 0.000 description 4
• 150000001413 amino acids Chemical class 0.000 description 4
• 239000006227 byproduct Substances 0.000 description 4
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
• 229910000024 caesium carbonate Inorganic materials 0.000 description 4
• 239000003054 catalyst Substances 0.000 description 4
• 238000004113 cell culture Methods 0.000 description 4
• 230000004663 cell proliferation Effects 0.000 description 4
• 239000003153 chemical reaction reagent Substances 0.000 description 4
• 230000000875 corresponding effect Effects 0.000 description 4
• 230000005284 excitation Effects 0.000 description 4
• 229940080856 gleevec Drugs 0.000 description 4
• 239000001963 growth medium Substances 0.000 description 4
• 229910052736 halogen Inorganic materials 0.000 description 4
• 229960002411 imatinib Drugs 0.000 description 4
• 230000004054 inflammatory process Effects 0.000 description 4
• 229910052740 iodine Inorganic materials 0.000 description 4
• 208000032839 leukemia Diseases 0.000 description 4
• 239000003446 ligand Substances 0.000 description 4
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
• 235000019341 magnesium sulphate Nutrition 0.000 description 4
• 230000003211 malignant effect Effects 0.000 description 4
• AVJOOVYAMFYHRS-UHFFFAOYSA-N n-(2,6-dichloro-3,5-dimethoxyphenyl)-3-(6-methylsulfinylpyrimidin-4-yl)pyrazin-2-amine Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=NC=CN=2)C=2N=CN=C(C=2)S(C)=O)=C1Cl AVJOOVYAMFYHRS-UHFFFAOYSA-N 0.000 description 4
• 229910000069 nitrogen hydride Inorganic materials 0.000 description 4
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
• 230000026731 phosphorylation Effects 0.000 description 4
• 238000006366 phosphorylation reaction Methods 0.000 description 4
• 125000006239 protecting group Chemical group 0.000 description 4
• 102000016914 ras Proteins Human genes 0.000 description 4
• 238000013207 serial dilution Methods 0.000 description 4
• 239000000377 silicon dioxide Substances 0.000 description 4
• 210000003491 skin Anatomy 0.000 description 4
• 229940086542 triethylamine Drugs 0.000 description 4
• 238000005406 washing Methods 0.000 description 4
• 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 3
• MVLGOVHEIMOSDV-UHFFFAOYSA-N 2-chloro-6-fluoro-3,5-dimethoxybenzoic acid Chemical compound COC1=CC(OC)=C(Cl)C(C(O)=O)=C1F MVLGOVHEIMOSDV-UHFFFAOYSA-N 0.000 description 3
• WNRGWPVJGDABME-UHFFFAOYSA-N 3,5-Dimethoxyaniline Chemical compound COC1=CC(N)=CC(OC)=C1 WNRGWPVJGDABME-UHFFFAOYSA-N 0.000 description 3
• QAWNEXYXZJNVGB-UHFFFAOYSA-N 4-[(6-bromopyridin-3-yl)methyl]morpholine Chemical compound C1=NC(Br)=CC=C1CN1CCOCC1 QAWNEXYXZJNVGB-UHFFFAOYSA-N 0.000 description 3
• 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 3
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
• 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 3
• 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 3
• 208000005623 Carcinogenesis Diseases 0.000 description 3
• PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 3
• 108010036949 Cyclosporine Proteins 0.000 description 3
• 102100023274 Dual specificity mitogen-activated protein kinase kinase 4 Human genes 0.000 description 3
• 101000779641 Homo sapiens ALK tyrosine kinase receptor Proteins 0.000 description 3
• 101001115395 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 4 Proteins 0.000 description 3
• 101000844245 Homo sapiens Non-receptor tyrosine-protein kinase TYK2 Proteins 0.000 description 3
• 206010061218 Inflammation Diseases 0.000 description 3
• 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 3
• 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 3
• 101100091501 Mus musculus Ros1 gene Proteins 0.000 description 3
• 241000699670 Mus sp. Species 0.000 description 3
• 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 3
• 102100032028 Non-receptor tyrosine-protein kinase TYK2 Human genes 0.000 description 3
• 101150056950 Ntrk2 gene Proteins 0.000 description 3
• 239000012826 P38 inhibitor Substances 0.000 description 3
• 108010068588 Platelet-Derived Growth Factor alpha Receptor Proteins 0.000 description 3
• 229920001213 Polysorbate 20 Polymers 0.000 description 3
• 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 3
• 101100091511 Rhizobium radiobacter ros gene Proteins 0.000 description 3
• 230000001594 aberrant effect Effects 0.000 description 3
• 208000006673 asthma Diseases 0.000 description 3
• 230000035578 autophosphorylation Effects 0.000 description 3
• 230000036952 cancer formation Effects 0.000 description 3
• 231100000504 carcinogenesis Toxicity 0.000 description 3
• 230000033077 cellular process Effects 0.000 description 3
• 229960001265 ciclosporin Drugs 0.000 description 3
• 229910052681 coesite Inorganic materials 0.000 description 3
• 229910052906 cristobalite Inorganic materials 0.000 description 3
• 230000002950 deficient Effects 0.000 description 3
• 230000004069 differentiation Effects 0.000 description 3
• 239000002158 endotoxin Substances 0.000 description 3
• 239000012467 final product Substances 0.000 description 3
• 238000009472 formulation Methods 0.000 description 3
• 239000012458 free base Substances 0.000 description 3
• 150000002367 halogens Chemical class 0.000 description 3
• 238000000338 in vitro Methods 0.000 description 3
• 230000001965 increasing effect Effects 0.000 description 3
• 238000011534 incubation Methods 0.000 description 3
• 230000002401 inhibitory effect Effects 0.000 description 3
• 239000000543 intermediate Substances 0.000 description 3
• 210000000265 leukocyte Anatomy 0.000 description 3
• 238000012417 linear regression Methods 0.000 description 3
• 229920006008 lipopolysaccharide Polymers 0.000 description 3
• 239000002609 medium Substances 0.000 description 3
• 108020004999 messenger RNA Proteins 0.000 description 3
• VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 3
• 239000003960 organic solvent Substances 0.000 description 3
• 230000002018 overexpression Effects 0.000 description 3
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
• 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 3
• 239000013641 positive control Substances 0.000 description 3
• 230000000770 proinflammatory effect Effects 0.000 description 3
• JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
• 238000001953 recrystallisation Methods 0.000 description 3
• 238000011160 research Methods 0.000 description 3
• 230000019491 signal transduction Effects 0.000 description 3
• 235000012239 silicon dioxide Nutrition 0.000 description 3
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
• 235000017557 sodium bicarbonate Nutrition 0.000 description 3
• 229910000104 sodium hydride Inorganic materials 0.000 description 3
• 210000000130 stem cell Anatomy 0.000 description 3
• 229910052682 stishovite Inorganic materials 0.000 description 3
• 239000000126 substance Substances 0.000 description 3
• YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 3
• 229940124597 therapeutic agent Drugs 0.000 description 3
• 238000002560 therapeutic procedure Methods 0.000 description 3
• 229910052905 tridymite Inorganic materials 0.000 description 3
• OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
• YWNJQQNBJQUKME-UHFFFAOYSA-N 2-bromo-5-methylpyridine Chemical compound CC1=CC=C(Br)N=C1 YWNJQQNBJQUKME-UHFFFAOYSA-N 0.000 description 2
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
• PDEXXTHEMNGLQV-UHFFFAOYSA-N 4,6-bis(methylsulfanyl)pyrimidine Chemical compound CSC1=CC(SC)=NC=N1 PDEXXTHEMNGLQV-UHFFFAOYSA-N 0.000 description 2
• XJPZKYIHCLDXST-UHFFFAOYSA-N 4,6-dichloropyrimidine Chemical compound ClC1=CC(Cl)=NC=N1 XJPZKYIHCLDXST-UHFFFAOYSA-N 0.000 description 2
• TXELSPZUGVLZON-UHFFFAOYSA-N 4-iodo-6-methylsulfanylpyrimidine Chemical compound CSC1=CC(I)=NC=N1 TXELSPZUGVLZON-UHFFFAOYSA-N 0.000 description 2
• 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 2
• OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 2
• 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
• 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
• 206010009944 Colon cancer Diseases 0.000 description 2
• 229930105110 Cyclosporin A Natural products 0.000 description 2
• 102100023401 Dual specificity mitogen-activated protein kinase kinase 6 Human genes 0.000 description 2
• KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
• 102000004190 Enzymes Human genes 0.000 description 2
• 108090000790 Enzymes Proteins 0.000 description 2
• 101150036586 FES gene Proteins 0.000 description 2
• 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
• 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
• 108010010803 Gelatin Proteins 0.000 description 2
• 208000034951 Genetic Translocation Diseases 0.000 description 2
• 101000624426 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 6 Proteins 0.000 description 2
• 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 2
• 101001051777 Homo sapiens Protein kinase C alpha type Proteins 0.000 description 2
• 101001050288 Homo sapiens Transcription factor Jun Proteins 0.000 description 2
• 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 2
• 101150026109 INSR gene Proteins 0.000 description 2
• TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
• 241000124008 Mammalia Species 0.000 description 2
• 229910021380 Manganese Chloride Inorganic materials 0.000 description 2
• GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 2
• 101150003567 Mapk12 gene Proteins 0.000 description 2
• 102000056243 Mitogen-activated protein kinase 12 Human genes 0.000 description 2
• 108700015929 Mitogen-activated protein kinase 12 Proteins 0.000 description 2
• 101100381649 Mus musculus Bik gene Proteins 0.000 description 2
• 101100381845 Mus musculus Blk gene Proteins 0.000 description 2
• 101100268066 Mus musculus Zap70 gene Proteins 0.000 description 2
• 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
• ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 2
• 206010029113 Neovascularisation Diseases 0.000 description 2
• 229910019213 POCl3 Inorganic materials 0.000 description 2
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
• 102000001393 Platelet-Derived Growth Factor alpha Receptor Human genes 0.000 description 2
• 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 2
• 108090000315 Protein Kinase C Proteins 0.000 description 2
• 102000003923 Protein Kinase C Human genes 0.000 description 2
• 102100024924 Protein kinase C alpha type Human genes 0.000 description 2
• 239000012980 RPMI-1640 medium Substances 0.000 description 2
• 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 2
• 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 2
• 101150105578 SAPK3 gene Proteins 0.000 description 2
• 229920002472 Starch Polymers 0.000 description 2
• RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
• 208000007536 Thrombosis Diseases 0.000 description 2
• 108091023040 Transcription factor Proteins 0.000 description 2
• 102000040945 Transcription factor Human genes 0.000 description 2
• 206010052779 Transplant rejections Diseases 0.000 description 2
• GCTFWCDSFPMHHS-UHFFFAOYSA-M Tributyltin chloride Chemical compound CCCC[Sn](Cl)(CCCC)CCCC GCTFWCDSFPMHHS-UHFFFAOYSA-M 0.000 description 2
• 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
• 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
• 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 2
• 239000012190 activator Substances 0.000 description 2
• 230000000735 allogeneic effect Effects 0.000 description 2
• 229910021529 ammonia Inorganic materials 0.000 description 2
• 230000001028 anti-proliverative effect Effects 0.000 description 2
• 239000008346 aqueous phase Substances 0.000 description 2
• 239000012131 assay buffer Substances 0.000 description 2
• 210000003719 b-lymphocyte Anatomy 0.000 description 2
• 230000008901 benefit Effects 0.000 description 2
• 210000004204 blood vessel Anatomy 0.000 description 2
• 239000002775 capsule Substances 0.000 description 2
• 230000003197 catalytic effect Effects 0.000 description 2
• 230000022131 cell cycle Effects 0.000 description 2
• 230000036755 cellular response Effects 0.000 description 2
• 230000001684 chronic effect Effects 0.000 description 2
• 210000001072 colon Anatomy 0.000 description 2
• 208000029742 colonic neoplasm Diseases 0.000 description 2
• 238000004440 column chromatography Methods 0.000 description 2
• 239000006071 cream Substances 0.000 description 2
• 238000011161 development Methods 0.000 description 2
• 230000018109 developmental process Effects 0.000 description 2
• 239000003085 diluting agent Substances 0.000 description 2
• BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 2
• 150000002009 diols Chemical class 0.000 description 2
• 231100000673 dose–response relationship Toxicity 0.000 description 2
• 150000002081 enamines Chemical class 0.000 description 2
• 238000007824 enzymatic assay Methods 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
• 239000000284 extract Substances 0.000 description 2
• 229940126864 fibroblast growth factor Drugs 0.000 description 2
• 230000004927 fusion Effects 0.000 description 2
• 239000000499 gel Substances 0.000 description 2
• 239000008273 gelatin Substances 0.000 description 2
• 229920000159 gelatin Polymers 0.000 description 2
• 235000019322 gelatine Nutrition 0.000 description 2
• 235000011852 gelatine desserts Nutrition 0.000 description 2
• 231100000024 genotoxic Toxicity 0.000 description 2
• 230000001738 genotoxic effect Effects 0.000 description 2
• 208000005017 glioblastoma Diseases 0.000 description 2
• 239000003102 growth factor Substances 0.000 description 2
• 238000010438 heat treatment Methods 0.000 description 2
• 210000003958 hematopoietic stem cell Anatomy 0.000 description 2
• 210000003630 histaminocyte Anatomy 0.000 description 2
• 230000002519 immonomodulatory effect Effects 0.000 description 2
• 230000028993 immune response Effects 0.000 description 2
• 210000000987 immune system Anatomy 0.000 description 2
• 230000001506 immunosuppresive effect Effects 0.000 description 2
• 238000001727 in vivo Methods 0.000 description 2
• 102000006495 integrins Human genes 0.000 description 2
• 108010044426 integrins Proteins 0.000 description 2
• 230000003993 interaction Effects 0.000 description 2
• 239000010410 layer Substances 0.000 description 2
• 239000012139 lysis buffer Substances 0.000 description 2
• 239000011565 manganese chloride Substances 0.000 description 2
• 235000002867 manganese chloride Nutrition 0.000 description 2
• ODTXQKMLYIPFJY-UHFFFAOYSA-N methyl 2,6-difluoro-3,5-dimethoxybenzoate Chemical compound COC(=O)C1=C(F)C(OC)=CC(OC)=C1F ODTXQKMLYIPFJY-UHFFFAOYSA-N 0.000 description 2
• DRTJHLOLUHCUSC-UHFFFAOYSA-N methyl 2-(6-methylsulfanylpyrimidin-4-yl)acetate Chemical compound COC(=O)CC1=CC(SC)=NC=N1 DRTJHLOLUHCUSC-UHFFFAOYSA-N 0.000 description 2
• HLWARVBOEGPPGB-UHFFFAOYSA-N methyl 2-formyl-3,5-dimethoxybenzoate Chemical compound COC(=O)C1=CC(OC)=CC(OC)=C1C=O HLWARVBOEGPPGB-UHFFFAOYSA-N 0.000 description 2
• YXUIOVUOFQKWDM-UHFFFAOYSA-N methyl 3,5-dimethoxybenzoate Chemical compound COC(=O)C1=CC(OC)=CC(OC)=C1 YXUIOVUOFQKWDM-UHFFFAOYSA-N 0.000 description 2
• 238000002156 mixing Methods 0.000 description 2
• 125000006203 morpholinoethyl group Chemical group [H]C([H])(*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 2
• 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 2
• 239000012452 mother liquor Substances 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
• 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 2
• 239000012299 nitrogen atmosphere Substances 0.000 description 2
• 239000002674 ointment Substances 0.000 description 2
• 231100000590 oncogenic Toxicity 0.000 description 2
• 230000002246 oncogenic effect Effects 0.000 description 2
• 230000003287 optical effect Effects 0.000 description 2
• 150000002894 organic compounds Chemical class 0.000 description 2
• 238000012261 overproduction Methods 0.000 description 2
• 230000003647 oxidation Effects 0.000 description 2
• 238000007254 oxidation reaction Methods 0.000 description 2
• 230000008506 pathogenesis Effects 0.000 description 2
• 239000012071 phase Substances 0.000 description 2
• 239000002243 precursor Substances 0.000 description 2
• 239000003755 preservative agent Substances 0.000 description 2
• 238000010926 purge Methods 0.000 description 2
• 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 description 2
• 230000002829 reductive effect Effects 0.000 description 2
• 230000004044 response Effects 0.000 description 2
• 208000037803 restenosis Diseases 0.000 description 2
• 238000010898 silica gel chromatography Methods 0.000 description 2
• 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 description 2
• 229960002930 sirolimus Drugs 0.000 description 2
• 210000000329 smooth muscle myocyte Anatomy 0.000 description 2
• 239000011780 sodium chloride Substances 0.000 description 2
• 159000000000 sodium salts Chemical class 0.000 description 2
• AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
• 235000019345 sodium thiosulphate Nutrition 0.000 description 2
• 239000003381 stabilizer Substances 0.000 description 2
• 235000019698 starch Nutrition 0.000 description 2
• UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
• 230000035882 stress Effects 0.000 description 2
• 239000000829 suppository Substances 0.000 description 2
• 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
• 230000001225 therapeutic effect Effects 0.000 description 2
• 230000000699 topical effect Effects 0.000 description 2
• 238000013518 transcription Methods 0.000 description 2
• 230000035897 transcription Effects 0.000 description 2
• 230000009466 transformation Effects 0.000 description 2
• 238000013519 translation Methods 0.000 description 2
• 230000005747 tumor angiogenesis Effects 0.000 description 2
• 210000004881 tumor cell Anatomy 0.000 description 2
• 230000004614 tumor growth Effects 0.000 description 2
• 210000004509 vascular smooth muscle cell Anatomy 0.000 description 2
• OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 1
• STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
• IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
• ZMKGDQSIRSGUDJ-VSROPUKISA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-30-propyl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,1 Chemical compound CCC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O ZMKGDQSIRSGUDJ-VSROPUKISA-N 0.000 description 1
• 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 1
• FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
• KVGZZAHHUNAVKZ-UHFFFAOYSA-N 1,4-Dioxin Chemical compound O1C=COC=C1 KVGZZAHHUNAVKZ-UHFFFAOYSA-N 0.000 description 1
• FIJKNTZDZYOAGB-UHFFFAOYSA-N 1-[4-[[6-[[6-[4-(2,6-dichloro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]methyl]piperazin-1-yl]-2-hydroxyethanone Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(CN4CCN(CC4)C(=O)CO)=CC=3)C=2)=C1Cl FIJKNTZDZYOAGB-UHFFFAOYSA-N 0.000 description 1
• FFHPXSVUVZJSNL-UHFFFAOYSA-N 1-[6-[[6-[3-(2,6-dichloro-3,5-dimethoxyanilino)pyrazin-2-yl]pyrimidin-4-yl]amino]pyridin-3-yl]ethanol Chemical compound COC1=CC(OC)=C(Cl)C(NC=2C(=NC=CN=2)C=2N=CN=C(NC=3N=CC(=CC=3)C(C)O)C=2)=C1Cl FFHPXSVUVZJSNL-UHFFFAOYSA-N 0.000 description 1
• YWENEVBVNPLSKO-UHFFFAOYSA-N 1-[6-[[6-[4-(2,6-difluoro-3,5-dimethoxyanilino)pyrimidin-5-yl]pyrimidin-4-yl]amino]pyridin-3-yl]ethanol Chemical compound COC1=CC(OC)=C(F)C(NC=2C(=CN=CN=2)C=2N=CN=C(NC=3N=CC(=CC=3)C(C)O)C=2)=C1F YWENEVBVNPLSKO-UHFFFAOYSA-N 0.000 description 1
• IDINUJSAMVOPCM-UHFFFAOYSA-N 15-Deoxyspergualin Natural products NCCCNCCCCNC(=O)C(O)NC(=O)CCCCCCN=C(N)N IDINUJSAMVOPCM-UHFFFAOYSA-N 0.000 description 1
• MLCNOCRGSBCAGH-UHFFFAOYSA-N 2,3-dichloropyrazine Chemical compound ClC1=NC=CN=C1Cl MLCNOCRGSBCAGH-UHFFFAOYSA-N 0.000 description 1
• AHKXIHJVTQDRJR-UHFFFAOYSA-N 2,6-difluoro-3,5-dimethoxybenzoic acid Chemical compound COC1=CC(OC)=C(F)C(C(O)=O)=C1F AHKXIHJVTQDRJR-UHFFFAOYSA-N 0.000 description 1
• XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
• BNOJXHCCDUFRJU-UHFFFAOYSA-N 2-chloro-3,5-dimethoxy-6-methylaniline Chemical compound COC1=CC(OC)=C(Cl)C(N)=C1C BNOJXHCCDUFRJU-UHFFFAOYSA-N 0.000 description 1
• KFJPTISIRGWMHB-UHFFFAOYSA-N 2-chloro-3,5-dimethoxy-6-methylbenzoic acid Chemical compound COC1=CC(OC)=C(Cl)C(C(O)=O)=C1C KFJPTISIRGWMHB-UHFFFAOYSA-N 0.000 description 1
• DWUDAQDTWOQOFL-UHFFFAOYSA-N 2-chloropyrimido[5,4-d]pyrimidine Chemical compound N1=CN=CC2=NC(Cl)=NC=C21 DWUDAQDTWOQOFL-UHFFFAOYSA-N 0.000 description 1
• FOEMIZSFFWGXHX-UHFFFAOYSA-N 2-methylsulfanylpyrimidine Chemical compound CSC1=NC=CC=N1 FOEMIZSFFWGXHX-UHFFFAOYSA-N 0.000 description 1
• 102100037263 3-phosphoinositide-dependent protein kinase 1 Human genes 0.000 description 1
• UYRPXKQKNDLQCQ-UHFFFAOYSA-N 4-chloro-5-(6-methylsulfanylpyrimidin-4-yl)pyrimidine Chemical group C1=NC(SC)=CC(C=2C(=NC=NC=2)Cl)=N1 UYRPXKQKNDLQCQ-UHFFFAOYSA-N 0.000 description 1
• 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
• 102100036009 5'-AMP-activated protein kinase catalytic subunit alpha-2 Human genes 0.000 description 1
• LLAXFGHJYCEPIL-UHFFFAOYSA-N 5-(6-methylsulfanylpyrimidin-4-yl)-1h-pyrimidin-6-one Chemical compound C1=NC(SC)=CC(C=2C(=NC=NC=2)O)=N1 LLAXFGHJYCEPIL-UHFFFAOYSA-N 0.000 description 1
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
• 101150019464 ARAF gene Proteins 0.000 description 1
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
• 102100034134 Activin receptor type-1B Human genes 0.000 description 1
• 206010001258 Adenoviral infections Diseases 0.000 description 1
• 229920001817 Agar Polymers 0.000 description 1
• 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
• 108020004774 Alkaline Phosphatase Proteins 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
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
• 241000416162 Astragalus gummifer Species 0.000 description 1
• 208000006386 Bone Resorption Diseases 0.000 description 1
• 241000283690 Bos taurus Species 0.000 description 1
• CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
• 206010006448 Bronchiolitis Diseases 0.000 description 1
• ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 description 1
• KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 1
• 102000043139 CK2 family Human genes 0.000 description 1
• 108091054872 CK2 family Proteins 0.000 description 1
• OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
• 102000004657 Calcium-Calmodulin-Dependent Protein Kinase Type 2 Human genes 0.000 description 1
• 108010003721 Calcium-Calmodulin-Dependent Protein Kinase Type 2 Proteins 0.000 description 1
• 102100022789 Calcium/calmodulin-dependent protein kinase type IV Human genes 0.000 description 1
• 241000283707 Capra Species 0.000 description 1
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
• 101710118321 Casein kinase I isoform alpha Proteins 0.000 description 1
• 102100034356 Casein kinase I isoform alpha-like Human genes 0.000 description 1
• 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 description 1
• 229940123587 Cell cycle inhibitor Drugs 0.000 description 1
• 206010008342 Cervix carcinoma Diseases 0.000 description 1
• 102100040428 Chitobiosyldiphosphodolichol beta-mannosyltransferase Human genes 0.000 description 1
• 208000015943 Coeliac disease Diseases 0.000 description 1
• 206010009900 Colitis ulcerative Diseases 0.000 description 1
• 102000000503 Collagen Type II Human genes 0.000 description 1
• 108010041390 Collagen Type II Proteins 0.000 description 1
• 229940126639 Compound 33 Drugs 0.000 description 1
• 229940126062 Compound A Drugs 0.000 description 1
• 208000002330 Congenital Heart Defects Diseases 0.000 description 1
• 208000014997 Crohn colitis Diseases 0.000 description 1
• 208000011231 Crohn disease Diseases 0.000 description 1
• 108010068192 Cyclin A Proteins 0.000 description 1
• 102000002427 Cyclin B Human genes 0.000 description 1
• 108010068150 Cyclin B Proteins 0.000 description 1
• 108010058545 Cyclin D3 Proteins 0.000 description 1
• 102000003909 Cyclin E Human genes 0.000 description 1
• 108090000257 Cyclin E Proteins 0.000 description 1
• 102100025191 Cyclin-A2 Human genes 0.000 description 1
• 108010024986 Cyclin-Dependent Kinase 2 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
• 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 1
• 102100036329 Cyclin-dependent kinase 3 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
• 102100026805 Cyclin-dependent-like kinase 5 Human genes 0.000 description 1
• CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
• FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
• FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
• FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
• 108020004414 DNA Proteins 0.000 description 1
• 230000005778 DNA damage Effects 0.000 description 1
• 231100000277 DNA damage Toxicity 0.000 description 1
• 230000033616 DNA repair Effects 0.000 description 1
• 230000006820 DNA synthesis Effects 0.000 description 1
• 108010031042 Death-Associated Protein Kinases Proteins 0.000 description 1
• 102100038605 Death-associated protein kinase 2 Human genes 0.000 description 1
• 102100038606 Death-associated protein kinase 3 Human genes 0.000 description 1
• 206010012689 Diabetic retinopathy Diseases 0.000 description 1
• 101150051221 Dl gene Proteins 0.000 description 1
• 201000010374 Down Syndrome Diseases 0.000 description 1
• 101100508533 Drosophila melanogaster IKKbeta gene Proteins 0.000 description 1
• 101100042886 Drosophila melanogaster snk gene Proteins 0.000 description 1
• 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 1
• 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 Proteins 0.000 description 1
• 102100023115 Dual specificity tyrosine-phosphorylation-regulated kinase 2 Human genes 0.000 description 1
• 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 1
• 206010058314 Dysplasia Diseases 0.000 description 1
• 102100021587 Embryonic testis differentiation protein homolog A Human genes 0.000 description 1
• 102100030011 Endoribonuclease Human genes 0.000 description 1
• 101710199605 Endoribonuclease Proteins 0.000 description 1
• 206010014824 Endotoxic shock Diseases 0.000 description 1
• 108010055196 EphA2 Receptor Proteins 0.000 description 1
• 108010055182 EphA5 Receptor Proteins 0.000 description 1
• 108010055334 EphB2 Receptor Proteins 0.000 description 1
• 102100030322 Ephrin type-A receptor 1 Human genes 0.000 description 1
• 102100030340 Ephrin type-A receptor 2 Human genes 0.000 description 1
• 102100021605 Ephrin type-A receptor 5 Human genes 0.000 description 1
• 102100031968 Ephrin type-B receptor 2 Human genes 0.000 description 1
• 102100031983 Ephrin type-B receptor 4 Human genes 0.000 description 1
• 241000402754 Erythranthe moschata Species 0.000 description 1
• 101100127166 Escherichia coli (strain K12) kefB gene Proteins 0.000 description 1
• 101100306202 Escherichia coli (strain K12) rpoB gene Proteins 0.000 description 1
• 241000206602 Eukaryota Species 0.000 description 1
• 208000009386 Experimental Arthritis Diseases 0.000 description 1
• 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 1
• 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 1
• 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 1
• 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 1
• 102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 description 1
• 206010016654 Fibrosis Diseases 0.000 description 1
• 101150048336 Flt1 gene Proteins 0.000 description 1
• GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
• 102100037859 G1/S-specific cyclin-D3 Human genes 0.000 description 1
• 206010018338 Glioma Diseases 0.000 description 1
• 206010018364 Glomerulonephritis Diseases 0.000 description 1
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
• 102000019058 Glycogen Synthase Kinase 3 beta Human genes 0.000 description 1
• 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 description 1
• 239000007818 Grignard reagent Substances 0.000 description 1
• 229910004373 HOAc Inorganic materials 0.000 description 1
• 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
• NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
• 102100032827 Homeodomain-interacting protein kinase 2 Human genes 0.000 description 1
• 241000282412 Homo Species 0.000 description 1
• 101000600756 Homo sapiens 3-phosphoinositide-dependent protein kinase 1 Proteins 0.000 description 1
• 101000783681 Homo sapiens 5'-AMP-activated protein kinase catalytic subunit alpha-2 Proteins 0.000 description 1
• 101000799189 Homo sapiens Activin receptor type-1B Proteins 0.000 description 1
• 101000974816 Homo sapiens Calcium/calmodulin-dependent protein kinase type IV Proteins 0.000 description 1
• 101000891557 Homo sapiens Chitobiosyldiphosphodolichol beta-mannosyltransferase 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
• 101000956149 Homo sapiens Death-associated protein kinase 3 Proteins 0.000 description 1
• 101001049990 Homo sapiens Dual specificity tyrosine-phosphorylation-regulated kinase 2 Proteins 0.000 description 1
• 101000898120 Homo sapiens Embryonic testis differentiation protein homolog A Proteins 0.000 description 1
• 101000938354 Homo sapiens Ephrin type-A receptor 1 Proteins 0.000 description 1
• 101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 description 1
• 101001066401 Homo sapiens Homeodomain-interacting protein kinase 2 Proteins 0.000 description 1
• 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 1
• 101000977771 Homo sapiens Interleukin-1 receptor-associated kinase 4 Proteins 0.000 description 1
• 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 1
• 101001005128 Homo sapiens LIM domain kinase 1 Proteins 0.000 description 1
• 101001063392 Homo sapiens Lymphocyte function-associated antigen 3 Proteins 0.000 description 1
• 101000573441 Homo sapiens Misshapen-like kinase 1 Proteins 0.000 description 1
• 101001052493 Homo sapiens Mitogen-activated protein kinase 1 Proteins 0.000 description 1
• 101000628949 Homo sapiens Mitogen-activated protein kinase 10 Proteins 0.000 description 1
• 101000878540 Homo sapiens Protein-tyrosine kinase 2-beta Proteins 0.000 description 1
• 101000606502 Homo sapiens Protein-tyrosine kinase 6 Proteins 0.000 description 1
• 101000798015 Homo sapiens RAC-beta serine/threonine-protein kinase Proteins 0.000 description 1
• 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
• 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 1
• 101000945096 Homo sapiens Ribosomal protein S6 kinase alpha-5 Proteins 0.000 description 1
• 101000826081 Homo sapiens SRSF protein kinase 1 Proteins 0.000 description 1
• 101000661821 Homo sapiens Serine/threonine-protein kinase 17A Proteins 0.000 description 1
• 101000880439 Homo sapiens Serine/threonine-protein kinase 3 Proteins 0.000 description 1
• 101000777293 Homo sapiens Serine/threonine-protein kinase Chk1 Proteins 0.000 description 1
• 101000777277 Homo sapiens Serine/threonine-protein kinase Chk2 Proteins 0.000 description 1
• 101001059443 Homo sapiens Serine/threonine-protein kinase MARK1 Proteins 0.000 description 1
• 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
• 101000601441 Homo sapiens Serine/threonine-protein kinase Nek2 Proteins 0.000 description 1
• 101000588540 Homo sapiens Serine/threonine-protein kinase Nek6 Proteins 0.000 description 1
• 101000987310 Homo sapiens Serine/threonine-protein kinase PAK 2 Proteins 0.000 description 1
• 101000987297 Homo sapiens Serine/threonine-protein kinase PAK 4 Proteins 0.000 description 1
• 101000665442 Homo sapiens Serine/threonine-protein kinase TBK1 Proteins 0.000 description 1
• 101000742982 Homo sapiens Serine/threonine-protein kinase WNK3 Proteins 0.000 description 1
• 101000914496 Homo sapiens T-cell antigen CD7 Proteins 0.000 description 1
• 101000716102 Homo sapiens T-cell surface glycoprotein CD4 Proteins 0.000 description 1
• 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
• 101000772231 Homo sapiens Testis-specific serine/threonine-protein kinase 1 Proteins 0.000 description 1
• 101000864342 Homo sapiens Tyrosine-protein kinase BTK Proteins 0.000 description 1
• 101001050476 Homo sapiens Tyrosine-protein kinase ITK/TSK Proteins 0.000 description 1
• 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 1
• 101001117146 Homo sapiens [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial Proteins 0.000 description 1
• 206010020751 Hypersensitivity Diseases 0.000 description 1
• 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
• 102100039137 Insulin receptor-related protein Human genes 0.000 description 1
• 102100027268 Interferon-stimulated gene 20 kDa protein Human genes 0.000 description 1
• 102100023533 Interleukin-1 receptor-associated kinase 4 Human genes 0.000 description 1
• 108090001005 Interleukin-6 Proteins 0.000 description 1
• 108090001007 Interleukin-8 Proteins 0.000 description 1
• 102000042838 JAK family Human genes 0.000 description 1
• 108091082332 JAK family Proteins 0.000 description 1
• 208000007766 Kaposi sarcoma Diseases 0.000 description 1
• ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
• 229930182816 L-glutamine Natural products 0.000 description 1
• FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
• OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
• 102100026023 LIM domain kinase 1 Human genes 0.000 description 1
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
• 239000012448 Lithium borohydride Substances 0.000 description 1
• 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
• 102100030984 Lymphocyte function-associated antigen 3 Human genes 0.000 description 1
• 206010025323 Lymphomas Diseases 0.000 description 1
• 102100034069 MAP kinase-activated protein kinase 2 Human genes 0.000 description 1
• 101710141394 MAP kinase-activated protein kinase 2 Proteins 0.000 description 1
• 102100028397 MAP kinase-activated protein kinase 3 Human genes 0.000 description 1
• 101710141393 MAP kinase-activated protein kinase 3 Proteins 0.000 description 1
• 229940124647 MEK inhibitor Drugs 0.000 description 1
• 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
• 108010058398 Macrophage Colony-Stimulating Factor Receptor Proteins 0.000 description 1
• 102100028123 Macrophage colony-stimulating factor 1 Human genes 0.000 description 1
• 206010025671 Malignant melanoma stage IV Diseases 0.000 description 1
• 229930195725 Mannitol Natural products 0.000 description 1
• 101150060694 Mapk13 gene Proteins 0.000 description 1
• 206010027476 Metastases Diseases 0.000 description 1
• 206010027458 Metastases to lung Diseases 0.000 description 1
• 102100026287 Misshapen-like kinase 1 Human genes 0.000 description 1
• 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 1
• 102100026931 Mitogen-activated protein kinase 10 Human genes 0.000 description 1
• 102000056248 Mitogen-activated protein kinase 13 Human genes 0.000 description 1
• 108700015928 Mitogen-activated protein kinase 13 Proteins 0.000 description 1
• 102100026888 Mitogen-activated protein kinase kinase kinase 7 Human genes 0.000 description 1
• HZQDCMWJEBCWBR-UUOKFMHZSA-N Mizoribine Chemical compound OC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 HZQDCMWJEBCWBR-UUOKFMHZSA-N 0.000 description 1
• 241001529936 Murinae Species 0.000 description 1
• 101100272634 Mus musculus Bmx gene Proteins 0.000 description 1
• 101100306001 Mus musculus Mst1r gene Proteins 0.000 description 1
• 101100297651 Mus musculus Pim2 gene Proteins 0.000 description 1
• 101100101259 Mus musculus Tyro3 gene Proteins 0.000 description 1
• 101710190051 Muscle, skeletal receptor tyrosine protein kinase Proteins 0.000 description 1
• 102100038168 Muscle, skeletal receptor tyrosine-protein kinase Human genes 0.000 description 1
• 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
• 102100030783 Myosin light chain kinase 3 Human genes 0.000 description 1
• 101710198035 Myosin light chain kinase, smooth muscle Proteins 0.000 description 1
• 108010052185 Myotonin-Protein Kinase Proteins 0.000 description 1
• 102100022437 Myotonin-protein kinase Human genes 0.000 description 1
• 108010052419 NF-KappaB Inhibitor alpha Proteins 0.000 description 1
• 102100039337 NF-kappa-B inhibitor alpha Human genes 0.000 description 1
• 101150111783 NTRK1 gene Proteins 0.000 description 1
• ZMKGDQSIRSGUDJ-UHFFFAOYSA-N NVa2 cyclosporine Natural products CCCC1NC(=O)C(C(O)C(C)CC=CC)N(C)C(=O)C(C(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(C)NC(=O)C(C)NC(=O)C(CC(C)C)N(C)C(=O)C(C(C)C)NC(=O)C(CC(C)C)N(C)C(=O)CN(C)C1=O ZMKGDQSIRSGUDJ-UHFFFAOYSA-N 0.000 description 1
• 229910020700 Na3VO4 Inorganic materials 0.000 description 1
• 241000772415 Neovison vison Species 0.000 description 1
• 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
• 101100202399 Oryza sativa subsp. japonica SAPK4 gene Proteins 0.000 description 1
• 206010031149 Osteitis Diseases 0.000 description 1
• 108020002230 Pancreatic Ribonuclease Proteins 0.000 description 1
• 102000005891 Pancreatic ribonuclease Human genes 0.000 description 1
• 208000031481 Pathologic Constriction Diseases 0.000 description 1
• 229930182555 Penicillin Natural products 0.000 description 1
• JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
• 108091005804 Peptidases Proteins 0.000 description 1
• 108010058514 Phosphate-Binding Proteins Proteins 0.000 description 1
• 102000006335 Phosphate-Binding Proteins Human genes 0.000 description 1
• 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
• 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
• 102100030485 Platelet-derived growth factor receptor alpha Human genes 0.000 description 1
• 101150011368 Plk2 gene Proteins 0.000 description 1
• 239000002202 Polyethylene glycol Substances 0.000 description 1
• 239000004365 Protease Substances 0.000 description 1
• 108010029485 Protein Isoforms Proteins 0.000 description 1
• 102000001708 Protein Isoforms Human genes 0.000 description 1
• 102100037787 Protein-tyrosine kinase 2-beta Human genes 0.000 description 1
• 102100039810 Protein-tyrosine kinase 6 Human genes 0.000 description 1
• 102100032315 RAC-beta serine/threonine-protein kinase Human genes 0.000 description 1
• 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 1
• 101710141955 RAF proto-oncogene serine/threonine-protein kinase Proteins 0.000 description 1
• 101150071831 RPS6KA1 gene Proteins 0.000 description 1
• 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
• 108010079933 Receptor-Interacting Protein Serine-Threonine Kinase 2 Proteins 0.000 description 1
• 102100022502 Receptor-interacting serine/threonine-protein kinase 2 Human genes 0.000 description 1
• 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 1
• 101150077555 Ret gene Proteins 0.000 description 1
• 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
• 102100039314 Rho-associated protein kinase 2 Human genes 0.000 description 1
• 101710088493 Rho-associated protein kinase 2 Proteins 0.000 description 1
• 102100033645 Ribosomal protein S6 kinase alpha-5 Human genes 0.000 description 1
• 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
• 102000014400 SH2 domains Human genes 0.000 description 1
• 108050003452 SH2 domains Proteins 0.000 description 1
• 229910006024 SO2Cl2 Inorganic materials 0.000 description 1
• 102100023010 SRSF protein kinase 1 Human genes 0.000 description 1
• 108010044012 STAT1 Transcription Factor Proteins 0.000 description 1
• 102000006381 STAT1 Transcription Factor Human genes 0.000 description 1
• 206010039491 Sarcoma Diseases 0.000 description 1
• 206010039710 Scleroderma Diseases 0.000 description 1
• 206010040070 Septic Shock Diseases 0.000 description 1
• 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 1
• 102100037955 Serine/threonine-protein kinase 17A Human genes 0.000 description 1
• 102100037628 Serine/threonine-protein kinase 3 Human genes 0.000 description 1
• 102100031081 Serine/threonine-protein kinase Chk1 Human genes 0.000 description 1
• 102100031075 Serine/threonine-protein kinase Chk2 Human genes 0.000 description 1
• 102100028921 Serine/threonine-protein kinase MARK1 Human genes 0.000 description 1
• 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
• 102100037703 Serine/threonine-protein kinase Nek2 Human genes 0.000 description 1
• 102100031401 Serine/threonine-protein kinase Nek6 Human genes 0.000 description 1
• 102100027939 Serine/threonine-protein kinase PAK 2 Human genes 0.000 description 1
• 102100027940 Serine/threonine-protein kinase PAK 4 Human genes 0.000 description 1
• 102100026715 Serine/threonine-protein kinase STK11 Human genes 0.000 description 1
• 101710181599 Serine/threonine-protein kinase STK11 Proteins 0.000 description 1
• 102100038192 Serine/threonine-protein kinase TBK1 Human genes 0.000 description 1
• 102100038115 Serine/threonine-protein kinase WNK3 Human genes 0.000 description 1
• 206010041067 Small cell lung cancer Diseases 0.000 description 1
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
• UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
• IOEJYZSZYUROLN-UHFFFAOYSA-M Sodium diethyldithiocarbamate Chemical compound [Na+].CCN(CC)C([S-])=S IOEJYZSZYUROLN-UHFFFAOYSA-M 0.000 description 1
• 235000021355 Stearic acid Nutrition 0.000 description 1
• 238000006619 Stille reaction Methods 0.000 description 1
• CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
• 229930006000 Sucrose Natural products 0.000 description 1
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
• UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
• 108010016672 Syk Kinase Proteins 0.000 description 1
• 102000000551 Syk Kinase Human genes 0.000 description 1
• 230000006052 T cell proliferation Effects 0.000 description 1
• 102100027208 T-cell antigen CD7 Human genes 0.000 description 1
• 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 1
• 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
• QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
• 102100029350 Testis-specific serine/threonine-protein kinase 1 Human genes 0.000 description 1
• ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical class [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
• 229920001615 Tragacanth Polymers 0.000 description 1
• 102100023132 Transcription factor Jun Human genes 0.000 description 1
• 239000007983 Tris buffer Substances 0.000 description 1
• 229920004890 Triton X-100 Polymers 0.000 description 1
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
• 102100022596 Tyrosine-protein kinase ABL1 Human genes 0.000 description 1
• 102100029823 Tyrosine-protein kinase BTK Human genes 0.000 description 1
• 102100023345 Tyrosine-protein kinase ITK/TSK Human genes 0.000 description 1
• 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 1
• 102100021125 Tyrosine-protein kinase ZAP-70 Human genes 0.000 description 1
• 201000006704 Ulcerative Colitis Diseases 0.000 description 1
• 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
• 108091008605 VEGF receptors Proteins 0.000 description 1
• 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
• 208000027418 Wounds and injury Diseases 0.000 description 1
• 101001001642 Xenopus laevis Serine/threonine-protein kinase pim-3 Proteins 0.000 description 1
• 108010046882 ZAP-70 Protein-Tyrosine Kinase Proteins 0.000 description 1
• GJWAPAVRQYYSTK-UHFFFAOYSA-N [(dimethyl-$l^{3}-silanyl)amino]-dimethylsilicon Chemical compound C[Si](C)N[Si](C)C GJWAPAVRQYYSTK-UHFFFAOYSA-N 0.000 description 1
• BTKMJKKKZATLBU-UHFFFAOYSA-N [2-(1,3-benzothiazol-2-yl)-1,3-benzothiazol-6-yl] dihydrogen phosphate Chemical compound C1=CC=C2SC(C3=NC4=CC=C(C=C4S3)OP(O)(=O)O)=NC2=C1 BTKMJKKKZATLBU-UHFFFAOYSA-N 0.000 description 1
• SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-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
• 239000002250 absorbent Substances 0.000 description 1
• 230000002745 absorbent Effects 0.000 description 1
• GPWHDDKQSYOYBF-UHFFFAOYSA-N ac1l2u0q Chemical compound Br[Br-]Br GPWHDDKQSYOYBF-UHFFFAOYSA-N 0.000 description 1
• DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
• XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 description 1
• 239000002671 adjuvant Substances 0.000 description 1
• 239000008272 agar Substances 0.000 description 1
• 235000010419 agar Nutrition 0.000 description 1
• 235000010443 alginic acid Nutrition 0.000 description 1
• 239000000783 alginic acid Substances 0.000 description 1
• 229920000615 alginic acid Polymers 0.000 description 1
• 229960001126 alginic acid Drugs 0.000 description 1
• 150000004781 alginic acids Chemical class 0.000 description 1
• 125000003545 alkoxy group Chemical group 0.000 description 1
• 150000003973 alkyl amines Chemical class 0.000 description 1
• 230000000172 allergic effect Effects 0.000 description 1
• 230000007815 allergy Effects 0.000 description 1
• 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
• SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
• 150000001409 amidines Chemical class 0.000 description 1
• 238000005576 amination reaction Methods 0.000 description 1
• 239000000908 ammonium hydroxide Substances 0.000 description 1
• 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
• 230000033115 angiogenesis Effects 0.000 description 1
• 238000002399 angioplasty Methods 0.000 description 1
• 150000001448 anilines Chemical class 0.000 description 1
• 238000010171 animal model Methods 0.000 description 1
• 229940046836 anti-estrogen Drugs 0.000 description 1
• 230000001833 anti-estrogenic effect Effects 0.000 description 1
• 239000002260 anti-inflammatory agent Substances 0.000 description 1
• 239000002246 antineoplastic agent Substances 0.000 description 1
• 230000001640 apoptogenic effect Effects 0.000 description 1
• 238000003782 apoptosis assay Methods 0.000 description 1
• 239000007864 aqueous solution Substances 0.000 description 1
• 239000003125 aqueous solvent Substances 0.000 description 1
• ZDQSOHOQTUFQEM-PKUCKEGBSA-N ascomycin Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C\C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](O)[C@H](OC)C1 ZDQSOHOQTUFQEM-PKUCKEGBSA-N 0.000 description 1
• ZDQSOHOQTUFQEM-XCXYXIJFSA-N ascomycin Natural products CC[C@H]1C=C(C)C[C@@H](C)C[C@@H](OC)[C@H]2O[C@@](O)([C@@H](C)C[C@H]2OC)C(=O)C(=O)N3CCCC[C@@H]3C(=O)O[C@H]([C@H](C)[C@@H](O)CC1=O)C(=C[C@@H]4CC[C@@H](O)[C@H](C4)OC)C ZDQSOHOQTUFQEM-XCXYXIJFSA-N 0.000 description 1
• 125000004429 atom Chemical group 0.000 description 1
• 208000010668 atopic eczema Diseases 0.000 description 1
• 230000001363 autoimmune Effects 0.000 description 1
• 201000004982 autoimmune uveitis Diseases 0.000 description 1
• 230000005784 autoimmunity Effects 0.000 description 1
• LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
• 229960002170 azathioprine Drugs 0.000 description 1
• 230000004888 barrier function Effects 0.000 description 1
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
• 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
• 125000004600 benzothiopyranyl group Chemical group S1C(C=CC2=C1C=CC=C2)* 0.000 description 1
• 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
• 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
• WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
• 239000011230 binding agent Substances 0.000 description 1
• 230000033228 biological regulation Effects 0.000 description 1
• 230000005540 biological transmission Effects 0.000 description 1
• 229960002685 biotin Drugs 0.000 description 1
• 239000011616 biotin Substances 0.000 description 1
• 230000037396 body weight Effects 0.000 description 1
• 238000009835 boiling Methods 0.000 description 1
• 230000014461 bone development Effects 0.000 description 1
• 210000001185 bone marrow Anatomy 0.000 description 1
• 210000002798 bone marrow cell Anatomy 0.000 description 1
• 208000024883 bone remodeling disease Diseases 0.000 description 1
• 230000024279 bone resorption Effects 0.000 description 1
• 210000000481 breast Anatomy 0.000 description 1
• 210000000069 breast epithelial cell Anatomy 0.000 description 1
• PHEZJEYUWHETKO-UHFFFAOYSA-N brequinar Chemical compound N1=C2C=CC(F)=CC2=C(C(O)=O)C(C)=C1C(C=C1)=CC=C1C1=CC=CC=C1F PHEZJEYUWHETKO-UHFFFAOYSA-N 0.000 description 1
• 229950010231 brequinar Drugs 0.000 description 1
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• 239000011575 calcium Substances 0.000 description 1
• 229910052791 calcium Inorganic materials 0.000 description 1
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
• 239000001768 carboxy methyl cellulose Substances 0.000 description 1
• 239000000969 carrier Substances 0.000 description 1
• 230000003915 cell function Effects 0.000 description 1
• 239000013592 cell lysate Substances 0.000 description 1
• 239000006285 cell suspension Substances 0.000 description 1
• 230000005754 cellular signaling Effects 0.000 description 1
• 239000001913 cellulose Substances 0.000 description 1
• 229920002678 cellulose Polymers 0.000 description 1
• 238000005119 centrifugation Methods 0.000 description 1
• 201000010881 cervical cancer Diseases 0.000 description 1
• 239000003638 chemical reducing agent Substances 0.000 description 1
• 230000035605 chemotaxis Effects 0.000 description 1
• 238000005660 chlorination reaction Methods 0.000 description 1
• 238000004587 chromatography analysis Methods 0.000 description 1
• 238000011097 chromatography purification Methods 0.000 description 1
• 208000037976 chronic inflammation Diseases 0.000 description 1
• 230000006020 chronic inflammation Effects 0.000 description 1
• 238000011260 co-administration Methods 0.000 description 1
• 229940126523 co-drug Drugs 0.000 description 1
• 238000000576 coating method Methods 0.000 description 1
• 239000003086 colorant Substances 0.000 description 1
• 230000000295 complement effect Effects 0.000 description 1
• 239000002299 complementary DNA Substances 0.000 description 1
• 229940125833 compound 23 Drugs 0.000 description 1
• 229940125878 compound 36 Drugs 0.000 description 1
• 229940125898 compound 5 Drugs 0.000 description 1
• 238000009833 condensation Methods 0.000 description 1
• 230000005494 condensation Effects 0.000 description 1
• 239000003636 conditioned culture medium Substances 0.000 description 1
• 208000028831 congenital heart disease Diseases 0.000 description 1
• 230000006552 constitutive activation Effects 0.000 description 1
• 230000002596 correlated effect Effects 0.000 description 1
• 239000003246 corticosteroid Substances 0.000 description 1
• 229960001334 corticosteroids Drugs 0.000 description 1
• 230000008878 coupling Effects 0.000 description 1
• 238000010168 coupling process Methods 0.000 description 1
• 238000005859 coupling reaction Methods 0.000 description 1
• 125000000753 cycloalkyl group Chemical group 0.000 description 1
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
• 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 1
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
• 229960004397 cyclophosphamide Drugs 0.000 description 1
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
• 229930182912 cyclosporin Natural products 0.000 description 1
• 108010019249 cyclosporin G Proteins 0.000 description 1
• 230000016396 cytokine production Effects 0.000 description 1
• 229940127089 cytotoxic agent Drugs 0.000 description 1
• 230000006378 damage Effects 0.000 description 1
• DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
• 238000006114 decarboxylation reaction Methods 0.000 description 1
• 230000003111 delayed effect Effects 0.000 description 1
• 230000002074 deregulated effect Effects 0.000 description 1
• 238000009795 derivation Methods 0.000 description 1
• 230000001066 destructive effect Effects 0.000 description 1
• 239000008121 dextrose Substances 0.000 description 1
• 125000006264 diethylaminomethyl group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
• LMBWSYZSUOEYSN-UHFFFAOYSA-N diethyldithiocarbamic acid Chemical compound CCN(CC)C(S)=S LMBWSYZSUOEYSN-UHFFFAOYSA-N 0.000 description 1
• 238000010790 dilution Methods 0.000 description 1
• 239000012895 dilution Substances 0.000 description 1
• OJKOHFRPOATBSE-UHFFFAOYSA-N dimethyl 2-(6-methylsulfanylpyrimidin-4-yl)propanedioate Chemical compound COC(=O)C(C(=O)OC)C1=CC(SC)=NC=N1 OJKOHFRPOATBSE-UHFFFAOYSA-N 0.000 description 1
• UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
• 239000007884 disintegrant Substances 0.000 description 1
• 238000006073 displacement reaction Methods 0.000 description 1
• 238000009826 distribution Methods 0.000 description 1
• CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
• 239000002552 dosage form Substances 0.000 description 1
• 230000007783 downstream signaling Effects 0.000 description 1
• 230000009977 dual effect Effects 0.000 description 1
• 230000004064 dysfunction Effects 0.000 description 1
• 230000002900 effect on cell Effects 0.000 description 1
• 239000012636 effector Substances 0.000 description 1
• 239000003995 emulsifying agent Substances 0.000 description 1
• 239000000839 emulsion Substances 0.000 description 1
• 210000003979 eosinophil Anatomy 0.000 description 1
• 210000000981 epithelium Anatomy 0.000 description 1
• 210000000267 erythroid cell Anatomy 0.000 description 1
• 239000000328 estrogen antagonist Substances 0.000 description 1
• DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
• 239000012091 fetal bovine serum Substances 0.000 description 1
• 239000012894 fetal calf serum Substances 0.000 description 1
• 230000001605 fetal effect Effects 0.000 description 1
• 230000004761 fibrosis Effects 0.000 description 1
• 239000000796 flavoring agent Substances 0.000 description 1
• 235000019634 flavors Nutrition 0.000 description 1
• 238000000684 flow cytometry Methods 0.000 description 1
• 239000012530 fluid Substances 0.000 description 1
• 229960002949 fluorouracil Drugs 0.000 description 1
• 108010003374 fms-Like Tyrosine Kinase 3 Proteins 0.000 description 1
• 235000003599 food sweetener Nutrition 0.000 description 1
• 125000000524 functional group Chemical group 0.000 description 1
• 125000002541 furyl group Chemical group 0.000 description 1
• 150000004795 grignard reagents Chemical class 0.000 description 1
• 150000004820 halides Chemical class 0.000 description 1
• 150000008282 halocarbons Chemical class 0.000 description 1
• 230000003862 health status Effects 0.000 description 1
• 201000011066 hemangioma Diseases 0.000 description 1
• 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 1
• 229960002050 hydrofluoric acid Drugs 0.000 description 1
• XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
• 229940071870 hydroiodic acid Drugs 0.000 description 1
• 206010020718 hyperplasia Diseases 0.000 description 1
• 230000003463 hyperproliferative effect Effects 0.000 description 1
• 239000005457 ice water Substances 0.000 description 1
• 125000002883 imidazolyl group Chemical group 0.000 description 1
• 230000036039 immunity Effects 0.000 description 1
• 238000007901 in situ hybridization Methods 0.000 description 1
• 238000000099 in vitro assay Methods 0.000 description 1
• 230000002779 inactivation Effects 0.000 description 1
• 238000010348 incorporation Methods 0.000 description 1
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
• 125000001041 indolyl group Chemical group 0.000 description 1
• 230000001939 inductive effect Effects 0.000 description 1
• 239000007972 injectable composition Substances 0.000 description 1
• 239000007924 injection Substances 0.000 description 1
• 238000002347 injection Methods 0.000 description 1
• 208000014674 injury Diseases 0.000 description 1
• 150000007529 inorganic bases Chemical class 0.000 description 1
• 108010054372 insulin receptor-related receptor Proteins 0.000 description 1
• 210000000936 intestine Anatomy 0.000 description 1
• 230000003834 intracellular effect Effects 0.000 description 1
• 230000004068 intracellular signaling Effects 0.000 description 1
• 239000011630 iodine Substances 0.000 description 1
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
• 239000000644 isotonic solution Substances 0.000 description 1
• 125000000842 isoxazolyl group Chemical group 0.000 description 1
• 239000008101 lactose Substances 0.000 description 1
• VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
• 229960000681 leflunomide Drugs 0.000 description 1
• 230000000670 limiting effect Effects 0.000 description 1
• 239000006210 lotion Substances 0.000 description 1
• 239000000314 lubricant Substances 0.000 description 1
• 238000004020 luminiscence type Methods 0.000 description 1
• 210000004072 lung Anatomy 0.000 description 1
• 201000005296 lung carcinoma Diseases 0.000 description 1
• 208000002780 macular degeneration Diseases 0.000 description 1
• 239000011777 magnesium Substances 0.000 description 1
• 229910001629 magnesium chloride Inorganic materials 0.000 description 1
• 159000000003 magnesium salts Chemical class 0.000 description 1
• 239000000594 mannitol Substances 0.000 description 1
• 235000010355 mannitol Nutrition 0.000 description 1
• 239000011159 matrix material Substances 0.000 description 1
• 238000002844 melting Methods 0.000 description 1
• 230000008018 melting Effects 0.000 description 1
• 239000012528 membrane Substances 0.000 description 1
• LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
• 230000009401 metastasis Effects 0.000 description 1
• 230000001394 metastastic effect Effects 0.000 description 1
• 206010061289 metastatic neoplasm Diseases 0.000 description 1
• LSDPWZHWYPCBBB-UHFFFAOYSA-M methanethiolate Chemical compound [S-]C LSDPWZHWYPCBBB-UHFFFAOYSA-M 0.000 description 1
• 229960000485 methotrexate Drugs 0.000 description 1
• PGRIMAJVMALBLI-UHFFFAOYSA-N methyl 2-chloro-3,5-dimethoxy-6-methylbenzoate Chemical compound COC(=O)C1=C(C)C(OC)=CC(OC)=C1Cl PGRIMAJVMALBLI-UHFFFAOYSA-N 0.000 description 1
• YYQYMDQPOSVVCE-UHFFFAOYSA-N methyl 2-chloro-6-fluoro-3,5-dimethoxybenzoate Chemical compound COC(=O)C1=C(F)C(OC)=CC(OC)=C1Cl YYQYMDQPOSVVCE-UHFFFAOYSA-N 0.000 description 1
• IALAUVYODBSDEV-UHFFFAOYSA-N methyl 2-fluoro-3,5-dimethoxybenzoate Chemical compound COC(=O)C1=CC(OC)=CC(OC)=C1F IALAUVYODBSDEV-UHFFFAOYSA-N 0.000 description 1
• 229920000609 methyl cellulose Polymers 0.000 description 1
• 239000001923 methylcellulose Substances 0.000 description 1
• 235000010981 methylcellulose Nutrition 0.000 description 1
• ZIYVHBGGAOATLY-UHFFFAOYSA-N methylmalonic acid Chemical compound OC(=O)C(C)C(O)=O ZIYVHBGGAOATLY-UHFFFAOYSA-N 0.000 description 1
• HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 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
• 229950000844 mizoribine Drugs 0.000 description 1
• 210000001616 monocyte Anatomy 0.000 description 1
• 230000037257 muscle growth Effects 0.000 description 1
• 206010028417 myasthenia gravis Diseases 0.000 description 1
• RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
• 229960000951 mycophenolic acid Drugs 0.000 description 1
• HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
• 210000000066 myeloid cell Anatomy 0.000 description 1
• 210000003914 myeloid leukocyte Anatomy 0.000 description 1
• BLUYEPLOXLPVCJ-INIZCTEOSA-N n-[(1s)-2-[4-(3-aminopropylamino)butylamino]-1-hydroxyethyl]-7-(diaminomethylideneamino)heptanamide Chemical compound NCCCNCCCCNC[C@H](O)NC(=O)CCCCCCNC(N)=N BLUYEPLOXLPVCJ-INIZCTEOSA-N 0.000 description 1
• JTSLALYXYSRPGW-UHFFFAOYSA-N n-[5-(4-cyanophenyl)-1h-pyrrolo[2,3-b]pyridin-3-yl]pyridine-3-carboxamide Chemical compound C=1C=CN=CC=1C(=O)NC(C1=C2)=CNC1=NC=C2C1=CC=C(C#N)C=C1 JTSLALYXYSRPGW-UHFFFAOYSA-N 0.000 description 1
• RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
• 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
• 210000000653 nervous system Anatomy 0.000 description 1
• 230000007514 neuronal growth Effects 0.000 description 1
• ZHCAAFJSYLFLPX-UHFFFAOYSA-N nitrocyclohexatriene Chemical group [O-][N+](=O)C1=CC=C=C[CH]1 ZHCAAFJSYLFLPX-UHFFFAOYSA-N 0.000 description 1
• 230000037311 normal skin Effects 0.000 description 1
• QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
• OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
• 102000027450 oncoproteins Human genes 0.000 description 1
• 108091008819 oncoproteins Proteins 0.000 description 1
• 150000007524 organic acids Chemical class 0.000 description 1
• 150000007530 organic bases Chemical class 0.000 description 1
• 210000004798 organs belonging to the digestive system Anatomy 0.000 description 1
• 230000003204 osmotic effect Effects 0.000 description 1
• 230000008723 osmotic stress Effects 0.000 description 1
• 201000008482 osteoarthritis Diseases 0.000 description 1
• 210000002997 osteoclast Anatomy 0.000 description 1
• 230000001009 osteoporotic effect Effects 0.000 description 1
• 210000001672 ovary Anatomy 0.000 description 1
• 125000002971 oxazolyl group Chemical group 0.000 description 1
• KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
• 239000007800 oxidant agent Substances 0.000 description 1
• 230000036961 partial effect Effects 0.000 description 1
• 239000006072 paste Substances 0.000 description 1
• 230000001575 pathological effect Effects 0.000 description 1
• 230000037361 pathway Effects 0.000 description 1
• 229940049954 penicillin Drugs 0.000 description 1
• 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
• 210000005259 peripheral blood Anatomy 0.000 description 1
• 239000011886 peripheral blood Substances 0.000 description 1
• 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
• 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
• 230000000144 pharmacologic effect Effects 0.000 description 1
• AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
• 229940080469 phosphocellulose Drugs 0.000 description 1
• FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
• 230000000704 physical effect Effects 0.000 description 1
• 125000004193 piperazinyl group Chemical group 0.000 description 1
• 125000003386 piperidinyl group Chemical group 0.000 description 1
• 210000004180 plasmocyte Anatomy 0.000 description 1
• 101150067958 plk-3 gene Proteins 0.000 description 1
• 125000003367 polycyclic group Chemical group 0.000 description 1
• 229920001223 polyethylene glycol Polymers 0.000 description 1
• 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
• 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
• 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
• 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
• TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
• 239000000843 powder Substances 0.000 description 1
• 239000002244 precipitate Substances 0.000 description 1
• 230000003449 preventive effect Effects 0.000 description 1
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
• 230000005522 programmed cell death Effects 0.000 description 1
• 230000002035 prolonged effect Effects 0.000 description 1
• XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• 208000023958 prostate neoplasm Diseases 0.000 description 1
• 238000000159 protein binding assay Methods 0.000 description 1
• 208000005069 pulmonary fibrosis Diseases 0.000 description 1
• 125000003226 pyrazolyl group Chemical group 0.000 description 1
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
• 125000000714 pyrimidinyl group Chemical group 0.000 description 1
• LQYCIOQCKLIHES-UHFFFAOYSA-N pyrimido[5,4-d]pyrimidin-2-amine Chemical compound N1=CN=CC2=NC(N)=NC=C21 LQYCIOQCKLIHES-UHFFFAOYSA-N 0.000 description 1
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
• 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
• 230000006340 racemization Effects 0.000 description 1
• 108700042226 ras Genes Proteins 0.000 description 1
• 230000009257 reactivity Effects 0.000 description 1
• 230000008439 repair process Effects 0.000 description 1
• 238000012552 review Methods 0.000 description 1
• 239000012266 salt solution Substances 0.000 description 1
• 201000000306 sarcoidosis Diseases 0.000 description 1
• 239000012047 saturated solution Substances 0.000 description 1
• 239000012363 selectfluor Substances 0.000 description 1
• 230000035945 sensitivity Effects 0.000 description 1
• 238000000926 separation method Methods 0.000 description 1
• 210000002966 serum Anatomy 0.000 description 1
• 239000012679 serum free medium Substances 0.000 description 1
• 230000007781 signaling event Effects 0.000 description 1
• 210000002027 skeletal muscle Anatomy 0.000 description 1
• 208000000587 small cell lung carcinoma Diseases 0.000 description 1
• 230000015590 smooth muscle cell migration Effects 0.000 description 1
• 239000011734 sodium Substances 0.000 description 1
• 229910052708 sodium Inorganic materials 0.000 description 1
• 235000015424 sodium Nutrition 0.000 description 1
• 239000012279 sodium borohydride Substances 0.000 description 1
• 229910000033 sodium borohydride Inorganic materials 0.000 description 1
• 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
• 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
• 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
• 239000012312 sodium hydride Substances 0.000 description 1
• RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
• 210000002023 somite Anatomy 0.000 description 1
• 239000000600 sorbitol Substances 0.000 description 1
• 239000012086 standard solution Substances 0.000 description 1
• 239000008107 starch Substances 0.000 description 1
• 239000008117 stearic acid Substances 0.000 description 1
• 230000036262 stenosis Effects 0.000 description 1
• 208000037804 stenosis Diseases 0.000 description 1
• 230000000638 stimulation Effects 0.000 description 1
• 229960005322 streptomycin Drugs 0.000 description 1
• 239000005720 sucrose Substances 0.000 description 1
• 150000003462 sulfoxides Chemical class 0.000 description 1
• 239000011593 sulfur Substances 0.000 description 1
• 208000014794 superficial urinary bladder carcinoma Diseases 0.000 description 1
• 239000006228 supernatant Substances 0.000 description 1
• 230000004083 survival effect Effects 0.000 description 1
• 239000003765 sweetening agent Substances 0.000 description 1
• 208000024891 symptom Diseases 0.000 description 1
• 230000002195 synergetic effect Effects 0.000 description 1
• QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
• 239000000454 talc Substances 0.000 description 1
• 229910052623 talc Inorganic materials 0.000 description 1
• 108091008743 testicular receptors 4 Proteins 0.000 description 1
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
• WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
• 125000003831 tetrazolyl group Chemical group 0.000 description 1
• 230000008719 thickening Effects 0.000 description 1
• 125000001544 thienyl group Chemical group 0.000 description 1
• 239000012443 tonicity enhancing agent Substances 0.000 description 1
• 239000000196 tragacanth Substances 0.000 description 1
• 235000010487 tragacanth Nutrition 0.000 description 1
• 229940116362 tragacanth Drugs 0.000 description 1
• 238000000844 transformation Methods 0.000 description 1
• 230000007704 transition Effects 0.000 description 1
• 238000011269 treatment regimen Methods 0.000 description 1
• 125000001425 triazolyl group Chemical group 0.000 description 1
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
• IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
• 238000013414 tumor xenograft model Methods 0.000 description 1
• 231100000588 tumorigenic Toxicity 0.000 description 1
• 230000000381 tumorigenic effect Effects 0.000 description 1
• 210000004026 tunica intima Anatomy 0.000 description 1
• 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
• 230000002792 vascular Effects 0.000 description 1
• 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 1
• 238000009736 wetting Methods 0.000 description 1
• 239000000080 wetting agent Substances 0.000 description 1