组蛋白甲基转移酶及其相应抑制剂在抗肿瘤领域的研究进展-张洁

ChineseJournalofNewDrugs2014235533201423581273545。[e-mail]。。[e-mail]。··201203。。。。Ｒ979．1A1003－3734201405－0533－08ProgressinresearchofhistonemethyltransferasesandtheirinhibitorsincancertreatmentZHANGJieDINGJianCHENYiDivisionofAntitumorPharmacologyStateKeyLaboratoryofDrugＲesearchShanghaiInstituteofMateriaMedicaChineseAcademyofSciencesShanghai201203ChinaAbstractAberranthistonemethylationregulatedbyabnormalhistonemethyltransferasesHMTshase-mergedasacriticalplayerintheonsetandprogressionofcancerinnumeroustumortypes．Thereversalofaberranthistonemethylationchangeshasthereforeemergedasapotentialstrategyforthetreatmentofcancer．AnumberofcompoundstargetingtheseHMTshavebeendevelopedasnoveltherapiesinwhichsomeareinclinicaltrials．ThisreviewhighlightstherolesofsomeHMTsintumorigenesisandemergingtherapiesbeingdevelopedforthetreatmentofcancer．KeywordshistonemethylationmodificationhistonemethyltransferasesHMTsanti-cancerdrugepi-genetics。H2AH2BH3H4147bdDNA1。DNA、、、2epigeneticmodification3。、、。DNA5-azacytidine2004FDAHDACiSAHA2006FDAT。。、、DNA。HistonetransferasesHMTsS-S-adenosylmethi-onineSAMSAMChineseJournalofNewDrugs20142355342014235。604、。。11．1histonelysinemethyltransferas-esHKMTshistonear-gininemethyltransferasesHＲMT。、、、。H39、20、27H34、36、795。DOT1LSuvarEnhancerofZesteTrithoraxSET。SET9p6527STAT31406－7G9ap53373p538。H3281726H3Ｒ2H3Ｒ8H3Ｒ17H3Ｒ26H43H4Ｒ3。IPＲMT1-4PＲMT6PＲMT8IIPＲMT5PＲMT7PＲMT99。PＲMT4glycine-and-arginine-richGAＲSAMGAＲ。PＲMT4---proline-glycine-methio-nine-andarginine-richPGM10。。PＲMT1DNAMＲE1111、53BP112。PＲMT1PＲMT4NF-κB13PＲMT5PＲMT614。、。、2004LSD1lysine-specificdemethylase1、15。LSD1H3K4H3K9。JmjCJmjC-domain-containing-demethylasesH3K4H3K36H3K9H3K27。16。1．2。。DNA、、DNA。。DNA。DNAHDACs。171。H3K27me3EZH2、、、ChineseJournalofNewDrugs20142355352014235EZH218－20。NSD2H3K36me221。H3K9me3Suv39h1。MllH3K4me222。。PＲMT4PＲMT123、、、、PＲMT51424－26PＲMT4。、。。、。127SUV39H1H3K9G9aH3K9、、MLLH3K4SETNSD1H3K36NSD1WHSC1H3K36H4K20WHSC1L1H3K4、DOT1LH3K79MLLSMYD3H3K4、、、EZH2H3K27、、、、、、、PＲC2SETD7H3K4SET7CAＲM1H3Ｒ17EP300-CBPNCOA3、22．1EZH2enhancerofzestehomolog2EZH2PＲC2PolycombＲepressiveComplex2H327。PＲC2。EZH2EEDSUZ12ＲbAp48AEBP2528EZH27q36．1292074630。EZH2PＲC2EEDSUZ1231。EZH2CSET、CXCNEIDEED-interactiondomaindomainIdomainII。EID。EZH2、H3K27me332。Soory-anarayanaVarambally、EZH2mＲNAEZH233。。EZH2EZH218。、、、ChineseJournalofNewDrugs20142355362014235、、、、、、EZH2。。BBEZH2H3K27me3。EZH2SETEZH2H3K27me3EZH2。Gor-icaNikoloskietal22%BdiffuselargeB-celllympho-masDLBCLs7%follicularlym-phomasFLsEZH2Y641F29。MichaelT．McCabe34100EZH2A677GH3K27。EZH2SETH3K27me3、EZH2。EZH2EpizymeEPZ00568735、EPZ-643836GlaxoSmithKlineGSKGSK12620NovartisEI137H3K27me3EZH2。SAMSAM。Epizyme。180000EPZ005687EPZ6438。EPZ005687EZH2EZH2IC50EZH2EZH150500。EPZ6438EZH220136I/II。EZH2。EPZ005687SMAＲCB1malignantrhabdoidtumorsMＲTs。GSKEZH2GSK126EZH2KAＲPAS-422NovartisEI1EZH2G1/S。EPZ6438GSK126EZH2EZH2EZH2。EZH2。2．2G9aG9aEHMT2KMT1C38。GLPSuv39h1chr6p21．31H39H3K9me238H3K9me、H3K9me3H3K2739。G9ap53Lys373p5340。G9aDNA38。G9aG9a9．5～12.5d41。G9a42、43、HIV44。G9a。、、、45－46G9a、47。G9aEpCAMH3K9me2EpCAM48。G9aSnailEMT49。G9aG9a。BIX01294G9aStefanKubicek12500050。ChineseJournalofNewDrugs20142355372014235G9a/GLPG9aIC501．7μmol·L－1。BIX012944．1μmol·L－1H3K9me2。G9a。UNCBIX012947-51。UNC063852UNC064253G9aIC50152．5nmol·L－1。GLPHMTsEZH2SUV39H1SUV39H2。UNC0638G9a/GLPH3K9me2IC5082nmol·L－152。UNC0642。BＲD4770G9aSAMSAMG9a。BＲD477010μmol·L－1H3K9me2H3K9me3G9a54。G9aG9aG9a。G9a。2．3DOT1LDOT1Ldisruptoroftelomericsilen-cing1-like55SET。H3K79H3K79me1H3K79me2H3K79me356－57。mixedlineageleukemiaMLLMLLDOT1LH3K79HOXA10MEIS158。DOT1LMLLDOT1L。EPZ0047759EpizymeSAMDOT1L。IC500．4±0.1nmol·L－1DOT1L1000。MLLEPZ00477H3K79me2。。EPZ00477EPZ-567660。EPZ-5676EZP00477I。33．1PＲMT3PＲMT3I61。PＲMT340SＲPS2ribosomalpro-teinS2ＲPS2GAＲＲNA62。PＲMT3ＲPS263。PＲMT364。PＲMT3DAL1。DAL1DAL165－67PＲMT3DAL1。Siarheyeva6816000PＲMT31-benzoD123thiadiazol-6-yl-3-2-cyclohexenylethylureaIC502．5μmol·L－1。IC50=480±10nmol·L－1PＲMT314u。14uPＲMT3PＲMT369。PＲMT3。3．2PＲMT4PＲMT4CAＲM1H321726。PＲMT4p300/CBPSＲC-370－71ＲNAPABP1Sam68HuDHuＲ72－73。PＲMT4mＲNA、DNAPＲMT4ChineseJournalofNewDrugs2014235538201423574。PＲMT4。PＲMT4AＲandrogenreceptorPＲMT413PＲMT4EＲestrogenreceptorMCF77575%PＲMT4PＲMT476。PＲMT4PＲMT4。N-Benzyl-1-heteroaryl-3-trifluoromethyl-1H-pyrazole-5-carboxamides7aPＲMT4IC5060nmol·L－1PＲMT4PＲMT110077。PＲMT47fPＲMT4IC5040nmol·L－1PＲMT1PＲMT3PＲMT410078PＲMT4。4、、。EZH2EPZ-6438DOT1LEPZ-5676。。。。DOT1LMLL。EZH2EZH2。。。EZH2EZH2EZH279。80EZH2DNADNA。7～10d。。。。。。1CHIPALLISCDWANGGG．Covalenthistonemodifications-miswrittenmisinterpretedandmis-erasedinhumancancersJ．NatＲevCancer2010107457－469．2SPAＲMANNAVL．Polycombsilencerscontrolcellfatedevelop-mentandcancerJ．NatＲevCancer2006611846－856．3FEINBEＲGAPTYCKOB．ThehistoryofcancerepigeneticsJ．NatＲevCancer200442143－153．4HELINKDHANAKD．ChromatinproteinsandmodificationsasdrugtargetsJ．Nature20135027472480－488．5STAＲKGＲWANGYLUT．Lysinemethylationofpromoter-boundtranscriptionfactorsandrelevancetocancerJ．CellＲes2011213375－380．6EAC-KBALTIMOＲED．ＲegulationofNF-kappaBactivitythroughlysinemonomethylationofp65J．PNAS20091064518972－1897