Mcl-1蛋白的结构,功能及其抑制剂的研究进展-孙凤娥

ChineseJournalofPharmaceuticals2013,443296apoptosisB-2Bcellleukemia-2Bcl-2Bcl-2Bcl-xl-1myeloidcellleukemia-1Mcl-1A1Mcl-1*250012Bcl-2Bcl-2Mcl-1Mcl-1Mcl-1Mcl-1Q51[e-mail][e-mail]ructure,FunctionandInhibitorsofMcl-1ProteinSUNFeng'e,FANGHao*Dept.ofMedicinalChemistry,SchoolofPharmacy,ShandongUniversity,Jinan250012ABSTRACT:Apoptosisiscloselyrelatedtotheoccurrenceofmanyhumandiseases.Excessiveapoptosiscausesneurodegenerativediseases,whileinsufficientapoptosisisrelatedtothegenerationofcancersandotherdiseases.Nowadays,Bcl-2familyproteinsarefoundtobeimportantinapoptosisregulationandmanyinhibitorsofBcl-2havebeeninvestigated.Recently,moreandmoreresearchersfocusonthestudiesofMcl-1,whichisamemberofBcl-2familyproteins,duetoitsuniqueroleintheapoptosispathway.ThispapersummarizesthestructureandfunctionofMcl-1,andtherecentprogressofMcl-1proteininhibitorsaspotentialantitumoragents.KeyWords:apoptosis;Mcl-1;structure;function;inhibitor;reviewBakBaxBH3-onlyBimBidNoxaPuma1Mcl-1Mcl-1Mcl-1Mcl-1Mcl-11Mcl-1Mcl-1ML-1Mcl-1Mcl-1ChineseJournalofPharmaceuticals2013,443297BTMcl-12Mcl-1STATSTAT5BCR/ABLMcl-1Mcl-1Bcl-235NPEST3PESTMcl-13Bcl-2Bcl-2homologyBHBH1BH3BH3Bcl-2Mcl-1CtransmembraneTM211Mcl-12Mcl-1Mcl-12Mcl-1BH3-onlyPumatBidBimBax/BakMcl-1BakBH3-onlyNoxaMcl-1BakPumaBakPumaccaspase4Mcl-1Mcl-11CDK-1PCNA53Mcl-1Bcl-2Bcl-xlMcl-110ABT-2636AT-1017ABT-737Bcl-2Mcl-12Mcl-1ChineseJournalofPharmaceuticals2013,443298Mcl-1RNAsiRNAABT-7378Mcl-1Mcl-13.1mRNAMcl-1ISIS20408Isis5'-TTGGCTTTGTGTCCTTGGCG-3'ISIS2040893.2BH3-onlyBH3-onlyNoxaMcl-1Chen10NoxaMcl-1Noxam3PAELEVECATQLRRIGDELNFRQKLLBcl-xlBcl-w2008Lee11BimBims2ADMRPEIWIAQEARRIGDEANAYYARRMcl-1Mcl-13.33.3.1gossypol1AT-1011Bcl-2Bcl-xlMcl-1Ki320480180nmol/LMcl-11BH31/CRPC21d20mg/d112ES-SCLC1371apogossypoloneApoG22Bcl-2Bcl-xlMcl-1Ki3566025nmol/LBcl-2Mcl-1Bcl-xl30PC-3DU-145MDA-MB-23l213612WSU-FSCCLIC50109nmol/LSCID2846313112IC50/mol·L112PC-36.11.0DU-1456.02.0MDA-MB-23l1.50.3ChineseJournalofPharmaceuticals2013,443299sabutoclaxBI-97C133Mcl-1Bcl-xlBcl-2A1IC500.200.310.320.62mol/L1415-7/-24mda-7/IL-243Mcl-1mda-7/IL-242006Wang16Mcl-1TW-374Bcl-2Bcl-xlMcl-1Ki2901110260nmol/L4PC-316---CHOP172WSU-DLCL2SCID4CHOP174TM-1206518BI-33619TM-179720Mcl-13.3.2GeminXobatoclaxGX15-0708Mcl-1Bcl-2Bcl-xlBcl-wMcl-1KD0.5mol/L8BakBaxMcl-1BakMcl-1ABT-737218//3.3.32004S19Mcl-1Mcl-1Bcl-2Mcl-1Ki31058nmol/L22Bcl-2/BimMcl-1/BakBcl-2/Bax23SKOV398hMcl-19Mcl-1SKOV3H2290.3mg/kg45ChineseJournalofPharmaceuticals2013,4433003.3.4maritoclax10MRSA24Mcl-1Mcl-1BimBcl-xl2510Mcl-1ABT-73725cryptosphaerolide11Cryptosphaeriasp.CNL-52311Mcl-1BakIC5011.4mol/LHCT-116IC504.5mol/L26Prakesch27MIPRALDEN12Mcl-1Bcl-xlKD2570mol/L2813BH3Bcl-2/BimBcl-xl/BimMcl-1/Bim3.4Mcl-1Mcl-1Mcl-129sorafenib14Mcl-1Mcl-1CLLimatinibmesylate15Mcl-lBcl-xlCMLK56230dasatinib16CMLSTAT5Mcl-131CDKflavopiridol17roscovitine18RNAIIMcl-132,334Mcl-1Mcl-1Mcl-1ChineseJournalofPharmaceuticals2013,4433012012JC0031MarzoI,NavalJ.Bcl-2familymembersasmoleculartargetsincancertherapyJ.BiochemPharmacol,2008,768:939-946.2AkgulC.Mcl-1isapotentialtherapeutictargetinmultipletypesofcancerJ.CellMolLifeSci,2008,668:1326-1336.3YangT,KozopasKM,CraigRW.TheintracellulardistributionandpatternofexpressionofMcl-1overlapwith,butarenotidenticalto,thoseofBcl-2J.JCellBiol,1995,1286:1173-1184.4ThomasLW,LamC,EdwardsSW.Mcl-1;themolecularregulationofproteinfunctionJ.FEBSLett,2010,58414:2981-2989.5JamilS,SoboutiR,HojabrpourP,etal.AproteolyticfragmentofMcl-1exhibitsnuclearlocalizationandregulatescellgrowthbyinteractionwithCdk1J.BiochemJ,2005,387Pt3:659-667.6GandhiL,CamidgeDR,RibeirodeOliveiraM,etal.PhaseIstudyofNavitoclaxABT-263,anovelBcl-2familyinhibitor,inpatientswithsmall-celllungcancerandothersolidtumorsJ.JClinOncol,2011,297:909-916.7BaggstromMQ,QiY,KoczywasM,etal.AphaseIIstudyofAT-101Gossypolinchemotherapy-sensitiverecurrentextensive-stagesmallcelllungcancerJ.JThoracOncol,2011,610:1757-1760.8KeulingAM,FeltonKE,ParkerAA,etal.RNAsilencingofMcl-1enhancesABT-737-mediatedapoptosisinmelanoma:roleforacaspase-8-dependentpathwayJ.PLoSOne,2009,48:e6651.9WacheckV,CejkaD,SieghartW,etal.Mcl-1isarelevantmoleculartargetforantisenseoligonucleotidestrategiesingastriccancercellsJ.CancerBiolTher,2006,510:1348-1354.10ChenL,WillisSN,WeiA,etal.DifferentialtargetingofprosurvivalBcl-2proteinsbytheirBH3-onlyligandsallowscomplementaryapoptoticfunctionJ.MolCell,2005,173:393-403.11LeeEF,CzabotarPE,VanDelftMF,etal.AnovelBH3ligandthatselectivelytargetsMcl-1revealsthatapoptosiscanproceedwithoutMcl-1degradationJ.JCellBiol,2008,1802:341-355.12LiuG,KellyWK,WildingG,etal.Anopen-label,multicenter,phaseI/IIstudyofsingle-agentAT-101inmenwithcastrate-resistantprostatecancerJ.ClinCancerRes,2009,159:3172-3176.13ArnoldAA,AboukameelA,ChenJ,etal.Preclinicalstudiesofapogossypolone:anewnonpeptidicpansmall-moleculeinhibitorofBcl-2,Bcl-XLandMcl-1proteinsinFollicularSmallCleavedCellLymphomamodelJ.MolCancer,ChineseJournalofPharmaceuticals2013,443302