酪氨酸激酶抑制剂的研究新进展[1]

:20016,:2001113e2mail:[e-mail]3(100080),,ATP:Q55517:A:10052281X(2002)0520355205ProgressinTyrosineKinaseInhibitorPengTao3ZhouJiaju(InstituteofProcessEngineering,ChineseAcademyofSciences,Beijing100080,China)AbstractProteintyrosinekinasesplayanimportantroleinsignaltransductionpathwaysinregulat2inganumberofcellularfunctions.Tyrosinekinasesareattractiveastargetsintheresearchoftherapeuticagents,notonlyagainstcancer,butalsoagainstmanyotherdiseases.Theprogressintyrosinekinasein2hibitorhasbeenreviewed,includingthechemicalstructuresandthepharmacophoremodels.Keywordstyrosinekinases;inhibitors;ATP;pharmacophoremodels(),,(TKs)[13]1980,HunterRNA(RSV)TK,ATPC,TK,(),,2000[4],10,,()TKTK,TK,10,,(EGFR),,,EGFR,(PDGFR)14520029PROGRESSINCHEMISTRYVol.14No.5Sep.,2002©1995-2006TsinghuaTongfangOpticalDiscCo.,Ltd.Allrightsreserved.(VEGFR)(FGFR)(IR)AblSrc,c2MetTrkJak2,,ATPATP,7,5ATPATP1981[5],,:,2,22[d]2[5,42d]2[2,32d]2[3,42d][6],Parke2Davis1994EGFR:PD153035,1[7],,[820]NovartisCGP52411,[2124]SugenPfizerAstraZeneca[2527]844,1,734,87%SU2101,2,1998,,PhaseÉ,2,3OONNHNBrPD153035OONHNHNHCGP524111PD153035CGP524111Novartis149AstraZeneca134Pfizer71Warner2Lambert(Parke2Davis)69Rhone2PoulencRorer59FarmitaliaCarloErba50Pharmacia&Upjohn44GlaxoWellcome36MitsubishiChemical34BoehringerIngelheim25Celltech24Sugen22KyowaHakko177342(IC50)NSC2330507PfizerphaseÉP1852431nMCGP257148NovartisphaseÉAbl,PDGFR38nM(Abl)ZD21839AstraZenecaphaseÊEGFR0.02mcMCP2358774PfizerphaseÊEGFR2nMSU25416SugenphaseÊFlk2120nMSDZ2LAP2977NovartisphaseÊHaCaT2050nM65314©1995-2006TsinghuaTongfangOpticalDiscCo.,Ltd.Allrightsreserved.2SU2101CGP593263ATP30ATPATP,EGFRTKFuretEGFRTKATPATP[28],cAMPATP,(CDK)2,cAMPXEGFR2TK422[2,32d]422[3,42d],Novartis,,[29],ATP5(1)EGFR,ATPN1N6(Gln767Met769),cAMPGlu121Val123CGP59326,NH(H)N1(H)()X,ATP,cAMPVal123(2),EGFR22CGP59326,ATP,Cys773SCys773EGFR,(3)ÉN7,EGFR,Thr766Thr860,,,CDKs,(CDK2Phe80)EGFRThr766öCGP59326,,(4)ÊATP,EGFR,Leu694Gly772,XFGFR(7535©1995-2006TsinghuaTongfangOpticalDiscCo.,Ltd.Allrightsreserved.CDK),Gly772(5),Parke2Davis422[2,32d]EGFRATP[30,31],ATPÉ,N1Met769(cAMPVal123),(N12):,2CDK2X,,TK,QSARQSAR,TK:,,[32],[33],Novartis2,42(2)26,722522,,ATP,,,,(),,[1]BurkerTR.DrugsFuture,1992,17:119131[2]FryDW.Exp.Opin.Invest.Drugs,1994,3:577595[3]TraxlerP,LydonN.DrugsFuture,1995,20:12611274[4]..:,1991.182[5]GrazianiY,ChayothR,KarnyN,etal.Biochem.Bio2phys.Acta,1981,714:415433[6](PangSH),(GuoZR).(ActaPharma.Sinica),1996,31(1):7580[7]FryDW,KrakerAJ,McMichaelA,etal.Science,1994,265:10931095[8]ShowalterH,SercelA,LejaB,etal.J.Med.Chem.,1997,40:413426[9]BredgesA,ZhouH,CodyD,etal.J.Med.Chem.,1996,39:267276[10]RewcastleG,PalmerB,BredgesA,etal.J.Med.Chem.,1996,39:918928[11]RewcastleG,PalmerB,ThompsonA,etal.J.Med.Chem.,1996,39:18231835[12]PalmerB,Trumpp2KallmeyerS,FryD,etal.J.Med.Chem.,1997,40:15191529[13]RewcastleG,BridgesA,FryD,etal.J.Med.Chem.,1997,40:18201826[14]ThompsonA,MurrayD,ElliottW,etal.J.Med.Chem.,1997,40:39153925[15]RewcastleG,MurrayD,ElliottW,etal.J.Med.Chem.,1998,41:742751[16]SmaillJ,PalmerB,RewcastleG,etal.J.Med.Chem.,1999,42:18031815[17]ShowalterH,GridgesA,ZhouH,etal.J.Med.Chem.,1999,42:54645474[18]SmaillJ,RewcastleG,LooJ,etal.J.Med.Chem.,2000,43:13801397[19]SmaillJ,ShowalterH,ZhouH,etal.J.Med.Chem.,2001,44:429440[20]BoschelliD,WuZ,KltchkoS,etal.J.Med.Chem.,1998,41:43654377[21]TraxlerP,GreenJ,MettH,etal.J.Med.Chem.,1999,42:1018102685314©1995-2006TsinghuaTongfangOpticalDiscCo.,Ltd.Allrightsreserved.[22]TraxlerP.Exp.Opin.Ther.Patents.,1997,7:571588[23]TraxlerP,FuretP,MettH,etal.J.Med.Chem.,1996,38:22852292[24]TraxlerP,BoldG,FreiJ,etal.J.Med.Chem.,1997,40:36013616[25]SunL,TranN,TangF,etal.J.Med.Chem.,1998,41:25882603[26]HennequinL,ThomasA,JohnstoneC,etal.J.Med.Chem.,1999,42:53695389[27](PangSH),(GuoZR),(LiangXT).(ActaPharma.Sinica),1997,32(7):515523[28]FuretP,CaravattiG,LydonN,etal.J.Comput.AidedMol.Des.,1995,9:465471[29]TraxlerP,FuretP.Phamacol.Ther.,1999,82:195206[30]PalmerBD,Trumpp2KallmeyerS,FryDW,etal.J.Med.Chem.,1997,40:15191529[31]Trumpp2KallmeyerS,RubinJR,HumbletC,etal.J.Med.Chem.,1998,41:17521763[32](GuoZR),(GotoS),(YangGZ).(ActaPharma.Sinica),1992,27(2):9095[33](LiaoN),(HouTJ),(ChenLR).(ComputerandAppliedChemistry),2000,17(1):37389535©1995-2006TsinghuaTongfangOpticalDiscCo.,Ltd.Allrightsreserved.