以bcl2蛋白家族为靶点的抗肿瘤药物设计

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1、以BCL-2蛋白家族为靶点的抗肿瘤药物设计Bcl-2FamilyProteinsasTherapeuticTargetsforanticancerdrugdesignDate:2013-05-231OutlineBackgroundHallmarksofCancerTheBcl-2ProteinFamilyModelofBH3mimetic-inducedapoptosisStructurebasisfordesigningligandsSmallmoleculeinhibitorsPeptidomimeticapp

2、roach—mimicthea-helixoftheBH3peptidesABT-737,ABT-263andtheiranalogspan-activeinhibitorofBcl-2SelectiveBcl-2inhibitorsselectiveBCL-xLinhibitorSelectiveMcl-1inhibitors2,Cell,144(5):646-674HallmarksofCancer3ExtrinsicandintrinsicpathwaysofapoptosisExpertOpin.Ther.P

3、atents(2012),22(1):37-554TheBcl-2ProteinFamilyTheBcl-2FamilyProteinswithanti-orpro-apoptoticfunctionCharacteristics:(Often)aC-terminaltransmembranedomain.Bcl-2homology(BH)domains.Bcl-2proteinsformhomo-andheterodimersviatheirBH-domainsBH1,BH2:Predictedtoformionc

4、hannelsBH3:The”suicidedomain”–regulatescelldeathBH4:Thoughttoconferanti-apoptoticactivity.(Chan&Yu.(2004).Clin.Exp.Pharmacol.Physiol.31:119).Chipuk,J.E，MolecularCell，2010，37(3):299-3105ElevatedofBcl-2orBcl-xLexpressionSeminarsinOncology,2004,30(Supplement16):13

5、3-142.6ModelofBH3mimetic-inducedapoptosis一、直接模型：抑制剂代替促凋亡蛋白BAK/BAX，与抗凋亡蛋白Bcl-2/Bcl-xl结合，从而抑制后者，促进细胞凋亡二、间接模型抑制剂替代特定的激活因子BH3-only蛋白，与抗调亡蛋白如BCL-2/BCL-xL结合，游离出来的BH3-only蛋白，激活BAK/BAX。NatureReviewsDrugDiscovery2008，7(12):989-1000ClinicalCancerResearch2009，15(4):1126-1

6、132.Oncogene，2009，27(S1):S149-S157.7Structurebasisfordesigningligands8ThemolecularbasisforheterodimerformationHeterodimerizationbetweenmembersoftheBcl-2familyofproteinsisakeyeventintheregulationofapoptosispro-apoptoticprotein(Bak)adoptsanamphipathica-helix(BH3d

7、omain)thatinteractswithanti-apoptoticproteins(Bcl-xl)throughhydrophobicandelectrostaticinteractionsinthehydrophobiccleft.9抗凋亡蛋白(BCL-2)是通过其表面疏水凹槽与促凋亡类(BIM)的BH3区域结合发生相互作用，调节细胞正常的生理凋亡。BCL-2familyantagonistsforcancertherapy.NatureReviewsDrugDiscovery2008，7(12):989-

8、1000OverlayofBCL-XL–ABT-737complexwithBCL-xlL–BIMBH3complexBcl-2andBIMBH310Bcl-xLandBak-BH3SurfacerepresentationofthebindingpocketofBcl-xLboundtotheBakpeptide11."Structureof