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新型蛋白激酶B小分子抑制剂的设计、合成和活性研究.docx

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新型蛋白激酶B小分子抑制剂的设计、合成和活性研究 Abstract ProteinkinaseB(PKB),alsoknownasAkt,isacriticalserine/threoninekinasethatplaysacrucialroleinvariouscellularfunctions,includingcellproliferation,survival,andmetabolism.DysregulatedPKBsignalingisimplicatedinamyriadofhumandiseases,includingcancer,diabetes,andcardiovasculardisease.Therefore,PKBhasbecomeavaluabletargetforthedevelopmentofsmall-moleculeinhibitors.Thispaperdiscussesthedesign,synthesis,andactivityofnewsmall-moleculeinhibitorsthattargetPKB. Introduction PKBisamemberoftheAGC(proteinkinaseA/proteinkinaseG/proteinkinaseC)familyofserine/threoninekinases.PKBisactivatedbyphosphatidylinositol3-kinase(PI3K),whichgeneratesphosphatidylinositol-3,4,5-trisphosphate(PIP3)fromphosphatidylinositol-4,5-bisphosphate(PIP2).PIP3recruitsPKBtotheplasmamembrane,whereitisphosphorylatedbyphosphoinositide-dependentkinase1(PDK1)atthreonine308(Thr308).ThisleadstoaconformationalchangethatexposestheregulatorydomainofPKB,whichisthenphosphorylatedatserine473(Ser473)bythemammaliantargetofrapamycincomplex2(mTORC2).ActivatedPKBthenphosphorylatesavarietyofdownstreamtargets,includingtranscriptionfactors,kinases,andothersignalingmolecules. PKBisbestknownforitsroleinpromotingcellsurvivalandgrowth.ActivatedPKBcanphosphorylateandinactivatethepro-apoptoticproteinBad,leadingtoincreasedsurvival.PKBcanalsotargetthetranscriptionfactorforkheadboxO(FOXO),whichpromotescellcyclearrestandapoptosis.Additionally,PKBcanactivatethemammaliantargetofrapamycin(mTOR),whichregulatesproteinsynthesisandcellproliferation.DysregulationofPKBsignalinghasbeenimplicatedinavarietyofhumandiseases,includingcancer,diabetes,andcardiovasculardisease.Therefore,PKBinhibitorshavethepotentialtobeusedastherapeuticagentstotreatthesediseases. DesignandSynthesisofPKBInhibitors ThedesignofnewPKBinhibitorshasbeenfacilitatedbytheavailabilityofcrystalstructuresofPKBincomplexwithsmall-moleculeinhibitors.ThesestructureshaveprovidedvaluableinsightsintothebindingmodesofPKBinhibitorsandhaveguidedtherationaldesignof