Imatinibisa2-phenylaminopyrimidinederivativethatfunctionsasaspecificinhibitorofanumberoftyrosinekinaseenzymes.ItoccupiestheTKactivesite,leadingtoadecreaseinactivity.TherearealargenumberofTKenzymesinthebody,includingtheinsulinreceptor.ImatinibisspecificfortheTKdomaininabl(theAbelsonproto-oncogene),c-kitandPDGF-R(platelet-derivedgrowthfactorreceptor).Inchronicmyelogenousleukemia,thePhiladelphiachromosomeleadstoafusionproteinofablwithbcr(breakpointclusterregion),termedbcr-abl.Asthisisnowacontinuouslyactivetyrosinekinase,imatinibisusedtodecreasebcr-ablactivity.TheactivesitesoftyrosinekinaseseachhaveabindingsiteforATP.TheenzymaticactivitycatalyzedbyatyrosinekinaseisthetransferoftheterminalphosphatefromATPtotyrosineresiduesonitssubstrates,aprocessknownasproteintyrosinephosphorylation.ImatinibworksbybindingtotheATPbindingsiteofbcr-ablandinhibitingtheenzymeactivityoftheproteincompetitively.Imatinibisquiteselectiveforbcr-abl–itdoesalsoinhibitothertargetsmentionedabove(c-kitandPDGF-R),butnootherknowntyrosinekinases.Imatinibalsoinhibitstheablproteinofnon-cancercellsbutcellsnormallyhaveadditionalredundanttyrosinekinaseswhichallowthemtocontinuetofunctionevenifabltyrosinekinaseisinhibited.Sometumorcells,however,haveadependenceonbcr-abl.Inhibitionofthebcr-abltyrosinekinasealsostimulatesitsentryintothenucleus,whereitisunabletoperformanyofitsnormalanti-apoptopicfunctions.
标签：Imatinib
