PROTAC-EZH2-Degrader-9-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEPROTACEZH2Degrader-9Cat.No.:HY-179499CASNo.:2978620-84-5分⼦式:C₅₁H₅₉N₇O₇分⼦量:882.06作⽤靶点:PROTACs;HistoneMethyltransferase;Apoptosis作⽤通路:PROTAC;Epigenetics;Apoptosis储存⽅式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY⽣物活性PROTACEZH2Degrader-9⼀种通过泛素-蛋⽩酶体途径发挥作⽤的⼝服有效的EZH2PROTAC降解剂。PROTACEZH2Degrader-9能下调PRC2核⼼亚并强效抑制H3K27me3，不响常见的CRBN新底物,且对GSPT1和IKZF1/3具有选择性。PROTACEZH2Degrader-9通过诱导细胞周期阻滞和细胞凋亡(apoptosis)对多种癌细胞系表现出强效的抗增殖活性。PROTACEZH2Degrader-9能逆转PRC2介导的因沉默，并抑制EZH2⾮催化靶因的激活。PROTACEZH2Degrader-9可⽤于⽩⾎病、淋巴瘤及⾮⼩细胞肺癌的研究[1]。IC50&TargetEZH2体外研究PROTACEZH2Degrader-9(compound5g)(0-10μM,0-48h)inducesthedegradationofEZH2independentontheubiquitin–proteasomesystemandthebindingtotheE3ligaseCRBNinMV4–11cells[1].PROTACEZH2Degrader-9(72h)hasantiproliferativeactivityinseveralcancer,includingMV4–11andMOLM-13(leukemia),SU-DHL-4andSU-DHL-6(largeB-celllymphoma),A549,NCI-H1299,andNCI-H1703(smallcelllungcancer)withIC50sof2.22,2.60,6.35,9.23,19.26,4.41,and6.35μM,respectively,exhibitsasignificantnegativecorrelationwiththeexpressionofEZH2(Pearsonr=−0.860,p=0.013)andCRBN(Pearsonr=−0.726,p=0.049)[1].PROTACEZH2Degrader-9(10μM,24h)exertsantiproliferativeactivitiesbydegradingEZH2andotherPRC2subunitsinNCI-H1299,NCI-H1703,MOLM-13,andA549cells[1].PROTACEZH2Degrader-9(10μM,72h)induces1,314differentiallyexpressedgeneswith657genesup-regulatedand657genesdownregulated,impactsseveralbiologicalprocesses,includingDNArepair,mitoticcellcycle,andG2/Mtransitionofmitoticcellcycle,enrichesdifferentiallyexpressedgenesincancer-relatedpathways,particularlythosegoverningthecellcycle,causenegativeenrichmentintheG2/Mcheckpointpathway,andpositiveenrichmentintheapoptosispathway[1].PROTACEZH2Degrader-9(0.12-10μM,24hand72h)causescellcyclearrestedintheG0/G1phase,1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEpreventingprogressionintoSandG2/Mphasesanddose-dependentlyinducesapoptosisinMV4–11cells[1].PROTACEZH2Degrader-9(1-10μM,72h)altersgeneexpressionsthatareregulatedbyEZH2catalyticandnon-catalyticactivitiesinMV4–11cells[1].WesternBlotAnalysis[1]CellLine:MV4–11cellsConcentration:0,0.06,0.13,0.25,0.5,1.0,3.0and10μMIncubationTime:0,0.5,1,2,4,8,24,48hResult:DecreasedPRC2levelswith10μMatdifferentdurations.DegradedEZH2,EED,SUZ12,andRbAp46proteinlevelswith10μMfor24and48h.InhibitedtheexpressionofH3K27me3at10μM24h,andachievedanalmostcompleteeliminationwith10μMfor48h.HadaminimalimpactonEZH2atlowconcentrationsof≤0.25μMhwithdifferentdurationsfor24h.InducedthedegradationofallPRC2coresubunits(EZH2,EED,SUZ12,andRbAp46)athigherconcentrations.ObservenoobviouschangesinproteinlevelsofGSPT1,IKZF1orIKZF3withdifferentconcentrationfor24h.ExhibitednoobviouseffectsonmRNAexpressionlevelsofEZH2,EED,SUZ12,andRbAp46ateither3or10μM.InduceddegradationofEZH2canbereversedbyMLN4924.WesternBlotAnalysis[1]CellLine:NCI-H1299,NCI-H1703,MOLM-13,andA549cellsConcentration:10μMIncubationTime:24hResult:InducedthedegradationofEZH2aswellasPRC2subunitsSUZ12,EED,andRbAp46ininNCI-H1299andNCI-H1703cells.WeaklyagainstEZH2anddecreasedPRC2subunitsinMOLM-13cells.HadnoobviousdegradationeffectonPRC2subunitsinA549cells.CellCycleAnalysis[1]CellLine:MV4–11cellsConcentration:0.12,0.37,1.11,3.33,10μMIncubationTime:24h2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEResult:Demonstratedasignificantdose-dependentriseincellpopulationsattheG0/G1phase,increasedto63.20%,64.61%,66.12%,69.89%,and73.60%atdifferentconcentration.RealTimeqPCR[1]CellLine:MV4-11cellsConcentration:1,3and10μMIncubationTime:72hResult:Up-regulatedthemRNAexpressionsofPRC2-dependentgenes,includingADRB2,CDKN2A,TXINP,andTNFRSF21inadose-dependentmanner.DownregulatedtheexpressionofseveralgenesknownastargetsofEZH2noncanonicalfunctions,includingARL6IP,BRIC5,CENPK,CHEK1,TACC3,TRAP,CDC25A,andE2F1.Notaffectedtheexpressionofc-Myc.REFERENCES[1].WeiW,etal.Design,synthesis,andbiologicalevaluationofabioavailableEZH2PROTACwitha2,8-diazaspiro[4.5]decanelinker.BioorgChem.