PROTAC-AR-Degrader-12-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEPROTACARDegrader-12Cat.No.:HY-179433分⼦式:C₅₇H₇₆N₈O₁₀S分⼦量:1065.33作⽤靶点:PROTACs;AndrogenReceptor;EstrogenReceptor/ERR;Src作⽤通路:PROTAC;VitaminDRelated/NuclearReceptor;ProteinTyrosineKinase/RTK储存⽅式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY⽣物活性PROTACARDegrader-12⼀种⾼效的PROTAC靶向雄激素受体(AR)共激活因⼦结合位点(AR-CBS)。PROTACARDegrader-12通过泛素-蛋⽩酶体系统(UPS)途径诱导AR降解。PROTACARDegrader-12通过响DNA复制和细胞分裂抑制肿瘤细胞⽣长。PROTACARDegrader-12不仅能有效降解AR，还能强效抑制MCF-7细胞以及多种突变或耐药乳腺癌细胞的增殖。PROTACARDegrader-12通过雌激素受体α(ERα)蛋⽩下调和转录活性抑制的双重机制有效阻断雌激素受体α(ERα)信号通路。PROTACARDegrader-12显著抑制FOXA1、GREB1、SRC和PELP1的mRNA表达。PROTACARDegrader-12可⽤于乳腺癌的研究[1]。IC50&TargetERα体外研究PROTACARDegrader-12(Compound18o)showsgoodinhibitoryactivityagainstMCF-7(IC50=0.13μM)andLCC2cells(IC50=0.54μM)andexhibitsbroad-spectrumefficacyagainstclinicallyrelevantmutantvariants,demonstratingpotentsubmicromolarinhibitionofMCF-7D538G(IC50=0.66μM),MCF-7Y537S(IC50=0.44μM),andMCF-7EGFR(IC50=0.52μM)[1].PROTACARDegrader-12(0.01-2μM,24h)effectivelyandinadose-dependentmannerdegradesARproteininMCF-7cells(DC50=0.72μM)[1].PROTACARDegrader-12(1μM,0-24h)showsatime-dependenteffectonARdegradationinMCF-7cells[1].PROTACARDegrader-12(0.01-2μM,24h)causesaconcentration-dependentdownregulationofERαproteininMCF-7cells[1].PROTACARDegrader-12(0.01-2μM,12-24h)significantlydownregulatesERαproteininMCF-7D538G,MCF-7Y537S,MCF-7EGFR,LCC2,andT47Dcells,andfailstodownregulateERβproteininPC9cells[1].PROTACARDegrader-12(1μM,24h)inducesadecreaseinERαthroughanindirectmechanism,ratherthanbydirectlytargetingthedegradationofCBSinMCF-7cells[1].1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEPROTACARDegrader-12(0-5μM,0-24h)reducesARproteininMCF-7cellsduetoposttranscriptionaldegradation,whilethereductioninERαwasaresultoftranscriptionalrepression[1].PROTACARDegrader-12exhibitspotentantiproliferativeactivityinAR-overexpressingbutERα-deficientprostatecancercellsLNCaP(IC50=0.46μM),whileitsantiproliferativeactivityissignificantlyreducedinAR-negativeMDA-MB-231cells(IC50>30μM)[1].PROTACARDegrader-12wasveryeffectiveinstabilizingtheARproteinathightemperature,whileitonlydisplaysaweakprotectiveeffectonERαprotein,suggestingthatcompoundPROTACARDegrader-12engagesARbutdoesnotbindtoErαinLCC2cells[1].PROTACARDegrader-12(1μM,24h)significantlyinhibitsthemRNAexpressionofFOXA1,GREB1,SRC,andPELP1inMCF-7cells[1].PROTACARDegrader-12(1-10μM,48h)inducesS-phasecellcyclearrestinMCF-7andLCC2cells[1].WesternBlotAnalysis[1]CellLine:MCF-7cellsConcentration:0.01μM,0.1μM,1μM,2μMIncubationTime:0h,3h,6h,12h,18h,24hResult:Effectivelyandinadose-dependentmannerdegradedARprotein.Time-dependenteffectonARdegradation.Causedaconcentration-dependentdownregulationofERαprotein.RealTimeqPCR[1]CellLine:MCF-7cellsConcentration:0μM,1μM,5μMIncubationTime:0h,4h,24hResult:ARmRNAexpressionincreasedsignificantlywithincreasingconcentration;ERαmRNAexpressionwasdownregulated.TheexpressionofERαtargetgenes(TFF1,PGR)andARtargetgenes(PSA,TMPRSS2)wassignificantlysuppressedafter24hours.SignificantlyinhibitedthemRNAexpressionofFOXA1,GREB1,SRC,andPELP1.体内研究PROTACARDegrader-12(Compound18o)(5-10μM/kg,i.p.,onceeveryotherday)significantlyinhibitstumorgrowthinMCF-7cellsandLCC2cellsxenograftmice,promotesARproteindegradationandERαsignalinginhibition,withoutweightlossorothertoxicities[1].AnimalModel:Balb/cnudemice(female,4weeksold)weresubcutaneouslyinjectedwithMCF-7humanbreastcancercells(5×106cells)[1].Dosage:5μM/kg,10μM/kg2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEAdministration:I.p.,onceeveryotherdayResult:Atadoseof10μM/kg,itsignificantlyinhibitedtumorgrowth.Tumorvolumedecreased,andKi67proliferationmarkerexpressionwasreduced.ARandERαproteinlevelsweredownregulatedintumortissue.Nosignificantchangeinbodyweightorsignificanttoxicitywasobserved.AnimalModel:Balb/cnudemice(female,4weeksold)weresubcutaneouslyinjectedwithtamoxifen-resistantLCC2humanbreastcancercells(5×106cells)[1].Dosage:5μM/kg,10μM/kgAdministration:I.p.,onceeveryotherdayResult:Tumorgrowthinhibitionrate(TGI)reached58%atadoseof10μM/kg.Ki67expressionwasdecreased,andARandERαproteinsweredownregulated.Bodyweightremainedstable,withnosignsoftoxicity.REFERENCES[1].WuY,etal.KillTwoBirdswithOneStone:AnEfficientandPotentARCBS-TargetedDegraderReversesBreastCancerResistanceviaConcurrentARDegradationandERαTranscriptionalSuppression