组蛋白去乙酰化酶6的结构-功能及选择性抑制剂的研究进展-刘仁帅

ActaPharmaceuticaSinica2015,50(1):7−1476,*(,250012):6(HDAC6),,HDAC6,HDAC6:;6;:R916:A:0513-4870(2015)01-0007-08Histonedeacetylase6:structure,functionsanddevelopmentofselectiveinhibitorsLIURen-shuai,FANGHao*(DepartmentofMedicinalChemistry,SchoolofPharmacy,ShandongUniversity,Jinan250012,China)Abstract:Histonedeacetylase6(HDAC6)isanuniquesubtypeofhistonedeacetylaseswithtwotandemdeacetylasedomainsandsubstratespecificityfornon-histoneproteins.Itisinvolvedinmanyimportantphysiologicalandpathologicalprocessesandhasbecomeapromisingtherapeutictargetinrecentdecades.DifferentkindsofpotentHDAC6-selectiveinhibitorshavebeenreportedaroundtheworld.ThispaperreviewstheprogressinthestudyofstructureandfunctionsofHDAC6aswellasthedevelopmentofHDAC6-selectiveinhibitors.Keywords:epigenetic;histonedeacetylase6;selectiveinhibitorDNA,,,,(histoneacetyltransferase,HAT)(histonedeacetylase,HDAC),418HDAC:I(HDAC13,8):2014-09-09;:2014-10-16.:(81373281);(NCET-12-0337);(JQ201319).*Tel:[phone],Fax:[phone],E-mail:[e-mail](IIa:HDAC4,5,7,9;IIb:HDAC6,10)III(SIRT17)IV(HDAC11)IIIIVZn2+;IIINAD+[1,2](HDACi)(ZBG)3,(vorinostat,1)(romidepsin,2)belinostat(3)(1)FDA,,[3]HDAC6,,HDAC6HDAC68ActaPharmaceuticaSinica2015,50(1):7−141FDAHDACi1HDAC6HDAC6Xp11.2223,21923bp,2841677bp[4]HDAC61215,HDACHDAC6(NLS)(NES1,NES2)(DD1,DD2)−(SE14)(ZnF-UBP)[5−9]NLS,NESSE14,HDAC6NESHDAC6,,SE14HDAC6[5],CDD2[7,8]ZnF-UBP(2)2HDAC62HDAC6,HDAC6,α-90(Hsp90)[10−14],HDAC6,HDAC6[15]α-HDAC6,[10]:HDAC6,;,HDAC6,,HDAC6,,[14]HDAC6Hsp90[11,12]Hsp90,HDAC6Hsp90[16],HDAC6[9,17],ataxin-3HDAC6HDAC6,,,;,1(HSF1),Hsp25Hsp70,,3HDAC6HDAC6[18,19],HDAC6,[20]HDAC6Ras,,,[21],HDAC6Hsp90,HDAC6,Hsp90,[22−24]HDAC6,,HDAC6α-,,;HDAC6,,HDAC6[25,26]HDAC6T,HDAC6T[26]4HDAC6HDAC6,,,:69HDAC6,HDAC6,HDAC64.1HDAC6Haggarty[27,28]2003tubacin(4)TubacinT,,tubacinHDAC1HDAC6HDAC8IIIHDAC[29]Tubacinα-,;,HDAC6dynein,[30]56tubacin,[31,32]51,2,3-HDAC6,;6HDAC656,6SAHA10Rocilinostat(ACY-1215,7)HDAC6[33],bortezomiblenalidomide(multiplemyeloma,MM),−,,8HDAC6,α3β,(one-bead-one-compound),HeLa[34]9HDAC6,(H460HCT-116)SAHA[35]4.2N-Smil[36]apicidin(10)HDAC6(11)HDAC6,RS;α-,H3,HDAC6TubastatinA(12)HDAC6,N-[37,38]tubastatinA13tubastatinA,tubastatinAFOXp3,T,[39]10ActaPharmaceuticaSinica2015,50(1):7−14NexturastatA(14)HPOB(15)N,N-Y[40,41]nexturastatA,N-,ZBGN-HDAC614B16;15SAHA,16μmol·L−115Blackburn[42]HDAC6,HDAC6,4--N-(16)16HDAC6,(100μmol·L−1),(pH7.52mmol·L−1)4.3N-SAHA[43]ST3595(17)HDAC6,[44]23-4-(18)HDAC6,:Vero,Aβ,[45]Lee[46]/N-HDAC7-19HDAC66-7-33%,HCT116SAHA:6114.4,(20)HDAC6[47−49]20αMCF-7,HDAC6,HDAC6[50]4.52,4'-(21)HDAC6,[51],,(22)[52]α,αR-,HDAC6[53]4.6IIHDAC[54],23,(HCT116t1/2=11h),HDAC6[55](24)HDAC6,HDAC1HDAC6[56]Inks[57]HDAC6(25)Michael,AML,NQN-1(25)Hsp90;Hsp90mutantFLT-3STAT5(26)HDAC6[58],αsp2HDAC65,HDAC6,HDAC6,HDAC6;HDAC6,;,,HDAC6,12ActaPharmaceuticaSinica2015,50(1):7−14References[1]ArrowsmithCH,BountraC,FishPV,etal.Epigeneticproteinfamilies:anewfrontierfordrugdiscovery[J].NatRevDrugDiscov,2012,11:384−400.[2]TanYM,HuangWY,YuNF.Structure-activityrelationshipsofhistonedeacetylaseinhibitors[J].ActaPharmSin(),2009,44:1072−1083.[3]BalasubramanianS,VernerE,BuggyJJ.Isoform-specifichistonedeacetylaseinhibitors:thenextstep?[J].CancerLett,2009,280:211−221.[4]MahlknechtU,SchnittgerS,LandgrafF,etal.Assignmentofthehumanhistonedeacetylase6gene(HDAC6)toXchromosomep11.23byinsituhybridization[J].CytogenetCellGenet,2001,93:135−136.[5]BertosNR,GilquinB,ChanGK,etal.Roleofthetetradecapeptiderepeatdomainofhumanhistonedeacetylase6incytoplasmicretention[J].JBiolChem,2004,279:48246−48254.[6]BoyaultC,SadoulK,PabionM,etal.HDAC6,atthecross-roadsbetweencytoskeletonandcellsignalingbyacetylationandubiquitination[J].Oncogene,2007,26:5468−5476.[7]ZhangY,GilquinB,KhochbinS,etal.Twocatalyticdomainsarerequiredforproteindeacetylation[J].JBiolChem,2006,281:2401−2404.[8]ZouH,WuY,NavreM,etal.Characterizationofthetwocatalyticdomainsinhistonedeacetylase6[J].BiochemBiophysResCommun,2006,341:45−50.[9]OuyangH,AliYO,RavichandranM,etal.Proteinaggregatesarerecruitedtoaggresomebyhistonedeacetylase6viaunanchoredubiquitinCtermini[J].JBiolChem,2012,287:2317−2327.[10]HubbertC,GuardiolaA,ShaoR,etal.HDAC6isamicrotubule-associateddeacetylase[J].Nature,2002,417:455−458.[11]BaliP,PranpatM,BradnerJ,etal.Inhibitionofhistonedeacetylase6acetylatesanddisruptsthechaperonefunctionofheatshockprotein90:anovelbasisforantileukemiaactivityofhistonedeacetylaseinhibitors[J].JBiolChem,2005,280:26729−26734.[12]KovacsJJ,MurphyPJ,GaillardS,etal.HDAC6regulatesHsp90acetylationandchaperone-dependentactivationofglucocorticoidreceptor[J].MolCell,2005,18:601−607.[13]TranAD,MarmoTP,SalamAA,etal.HDAC6deacetylationoftubulinmodulatesdynamicsofcellularadhesions[J].JCellSci,2007,120:1469−1479.[14]ZhangX,YuanZ,ZhangY,etal.HDAC6modulatescellmotilitybyalteringtheacetylationlevelofcortactin[J].MolCell,2007,27:197−213.[15]PalijanA,FernandesI,BastienY,etal.Functionofhistonedeacetylase6asacofactorofnuclearreceptorcoregulatorLCoR[J].JBiolChem,2009,284:30264−30274.[16]EcklJM,RichterK.FunctionsoftheHsp90chaperonesy