AR-Degrader-3-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors • ScreeningLibraries • Proteinswww.MedChemEARDegrader-3Cat.No.:HY-178938CASNo.:1182011-65-9分子式:C₂₃H₂₁N₃O₄S分子量:435.5作用靶点:MolecularGlues;AndrogenReceptor;Caspase;Apoptosis作用通路:PROTAC;VitaminDRelated/NuclearReceptor;Apoptosis储存方式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY生物活性ARDegrader-3一种具有口服活性的分子胶(molecularglue)，靶向AR/ARV7,通过泛素-蛋白酶体途径(UPP)诱导AR和ARV7降解。ARDegrader-3可直接与AR的配体结合域(LBD)和N端结构域(NTD)相互作。ARDegrader-3能有效抑制野生型AR(AR-WT)、AR突变体和ARV7的转录活性。ARDegrader-3可下调下游AR靶基因的mRNA和蛋白水平，从而克服由ARV7和AR点突变介导的抗雄激素耐药性。ARDegrader-3可诱导Enzalutamide(HY-70002)(ENZa)耐药细胞凋亡(apoptosis)，并增加裂解型caspase-3蛋白的水平。ARDegrader-3可用于去势抵抗性前列腺癌(CRPC)的研究[1]。IC50&TargetCaspase-3体外研究ARDegrader-3(CompoundA6)(0.2-5μM,24h)broadlyinhibitsARtranscriptionalactivitybydose-dependentlysuppressingbothexogenousandendogenousARinPC-3andC4-2cells;additionally,itsignificantlysuppressesendogenousARandARV7inENZa-resistant22Rv1cells,andinhibitsthetranscriptionalactivitiesofARmutants(W741L,T877A,F876L)inPC-3cells[1].ARDegrader-3(0.078-10μM,0-36h)dose-dependentlysuppressesARV7(DC50=0.24μM)proteinlevelin22Rv1cells,powerfullydown-regulatesAR(DC50=0.18μM)proteinlevelinC4-2cells,anddown-regulatesARV7proteinlevelsinatime-dependentmanner[1].ARDegrader-3potentlyinhibitsARandARV7bydirectlybindingtobothAR-LBD(IC50=105.4nM)andAR-AF1(KD=23.0μM)inLNCaPcells[1].ARDegrader-3(1-5μM,4-8h)degradesARandARV7throughtheubiquitin-proteasomepathway(UPP),asevidencedbyitsdose-dependentreductionofARandARV7proteinbutnotmRNAlevelsinC4-2and22Rv1cells,respectively;bydemonstratingaccelerateddegradationuponcycloheximidetreatment;byshowingthattheproteinlevelreductionwascounteractedbyMG132;andbymarkedlyinducingARubiquitination[1].ARDegrader-3(72h)inhibitstheproliferationofC4-2cells(IC50=0.59μM)and22Rv1cells(IC50=1.4μ1/3 MasterofBioactiveMolecules—您身边的抑制剂大师www.MedChemEM),buthaslittleeffectonDU145(IC50>50μM)andPC-3(IC50=48.6μM)cells[1].ARDegrader-3(0.2-5μM,8-24h)blocksR1881-inducedPSAproteinexpressioninadose-dependentmannerandreducesthemRNAlevelsofPSAandPMEPA1in22Rv1cells[1].ARDegrader-3(1-2μM,14days)selectivelydecreases22Rv1cellscolonynumbersbutshowsnoinfluenceonAR-negativePC-3cellscolonynumbersandpromotestheapoptosisofthe22Rv1cells[1].WesternBlotAnalysis[1]CellLine:22Rv1cellsConcentration:5μMIncubationTime:24hResult:SignificantlydownregulatedthelevelofARV7.WesternBlotAnalysis[1]CellLine:22Rv1cells,C4-2cellsConcentration:0.078μM,0.156μM,0.31μM,0.62μM,1.25μM,2.5μM,5μM,10μMIncubationTime:24hResult:Dose-dependentlysuppressedARV7(DC50=0.24μM)proteinlevelin22Rv1cells,down-regulatedAR(DC50=0.18μM)proteinlevelinC4-2cells.WesternBlotAnalysis[1]CellLine:22Rv1cellsConcentration:0.2μM,1μM,5μMIncubationTime:24hResult:BlockedR1881-inducedPSAproteinexpressioninadose-dependentmannerin22Rv1cells.RT-PCR[1]CellLine:22Rv1cellsConcentration:0.2μM,1μM,5μMIncubationTime:8hResult:ReducedthemRNAlevelofPSAin22Rv1cells.RT-PCR[1]2/3 MasterofBioactiveMolecules—您身边的抑制剂大师www.MedChemECellLine:22Rv1cellsConcentration:0.2μM,1μM,5μMIncubationTime:24hResult:ReducedthemRNAlevelofPMEPA1in22Rv1cells.CellProliferationAssay[1]CellLine:22Rv1cells,PC-3cellsConcentration:1μM,2μMIncubationTime:14daysResult:Decreased22Rv1cellscolonynumbersbutshowednoinfluenceonAR-negativePC-3cellscolonynumbers.体内研究ARDegrader-3(CompoundA6)(15-30mg/kg,p.o.,oncedailyfor14days)effectivelyinhibitsthegrowthofCRPCtumorsin22Rv1cellxenograftmiceinvivo,andnosignificanttoxicityisobserved[1].AnimalModel:MaleBALB/cnudemice(5-week-old)weresubcutaneouslyinoculatedwith5×10622Rv1cells[1].Dosage:15mg/kg,30mg/kgAdministration:P.o.,oncedailyfor14daysResult:Suppressed22Rv1tumorprogression.Showednochangeinbodyweight.SignificantlydecreasedARlevelsinthetumortissues.REFERENCESZhangR,etal.DevelopmentofdualAR/ARV7degraderswith3,5-dimethylisoxazoletoovercomeantiandrogenresistanceincastration-resistantprostatecancer.EurJMedChem.2026Jan