PROTAC-PI3Kα-degrader-1-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors • ScreeningLibraries • Proteinswww.MedChemEPROTACPI3Kαdegrader-1Cat.No.:HY-174461分子式:C₄₆H₄₉F₂N₇O₈S分子量:897.99作用靶点:PROTACs;PI3K作用通路:PROTAC;PI3K/Akt/mTOR储存方式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY生物活性PROTACPI3Kαdegrader-1是一种PI3Kα的PROTAC降解剂(DC50=0.08μM)，其对PI3Kα的降解作用表现出显著的选择性，相较于PI3Kβ、PI3Kγ和PI3Kδ亚型具有明显优势。PROTACPI3Kαdegrader-1以时间和浓度依赖性方式有效降解PI3Kα，并有效抑制Ser473位点AKT的磷酸化。PROTACPI3Kαdegrader-1在HGC-27和DOHH2异种移植模型中显示出显著的体内抗癌功效。(粉色：PI3Kα配体：(HY-174798)，蓝色：E3连接酶CRBN配体(HY-10984)，黑色：连接子，E3连接酶配体-接头偶联物：HY-W940885)[1]。IC50&TargetCereblonPI3KαPI3KβPI3Kγ62nM(IC50)293.94nM(IC50)>10000nM(IC50)PI3Kδ42.10(IC50)体外研究PROTACPI3Kαdegrader-1(Compound12)(1μM)showsnegligibleactivityagainst79kinases(<20%inhibition)whileexhibitspotentinhibitionofPIK3CA(＞95%)inT47Dbreastcancercells[1].PROTACPI3Kαdegrader-1(0.1-10μM)demonstratesgoodselectivityforPI3KαdegradationoverPI3Kβ,PI3KγandPI3KδinT47Dbreastcancercells[1].PROTACPI3Kαdegrader-1exhibitsexcellentselectivityforthedegradationofPI3Kαinvariouscancercelllines,withIC50sof0.35μM(T47D),1.64μM(MDA-MB-453),1.45μM(HGC-27),0.37μM(AGS),3.38μM(LNCaP),1.48μM(PC3)and0.69μM(Pfeiffer)[1].PROTACPI3Kαdegrader-1(0.0032-10μM,0-24h)degradesPI3Kαinaconcentration-andtime-dependentmannerinT47DandHGC-27cells[1].PROTACPI3Kαdegrader-1(1μM,20h)degradesPI3Kαviatheubiquitin-proteasomepathwaythroughCRBNrecruitmentinT47Dcells[1].PROTACPI3Kαdegrader-1(0.1-10μM,24h)inducescellcyclearrestattheG2/Mphaseconcentration-1/3 MasterofBioactiveMolecules—您身边的抑制剂大师www.MedChemEdependentlyinT47Dcells[1].WesternBlotAnalysis[1]CellLine:T47DcellsConcentration:1μMIncubationTime:20hwith/withoutMG132(HY-13259)(1μM)Result:ReducedthelevelofPI3Kα,whiletheadditionofMG132restoredPI3Kαlevels.RT-PCR[1]CellLine:T47DcellsConcentration:1μMIncubationTime:24hResult:DidnotdecreasethemRNAlevelsofPIK3CA.WesternBlotAnalysis[1]CellLine:T47DcellsConcentration:1μMIncubationTime:8hafterThalidomide(HY-14658)(10μM)preincubated1handthenincubatedinfreshmediumforanadditional48hours.Result:DegradedPI3Kαbutpreincubationwiththalidomide(10μM,1h)reducedthisdegradation.RestoredPI3Kαexpressiontonormallevels48hafteran8htreatmentfollowedbyincubationinfreshmedium.体内研究PROTACPI3Kαdegrader-1(Compound12)(2μM,0-60min)showssuperiorplasmastabilityacrossallofthetestedspeciesincludingmice,rats,dogs,monkeys,andhuman[1].PROTACPI3Kαdegrader-1(2μM,0-60min)exhibitsmoderatetohighclearanceratesineachspecies,withhalf-life(t1/2)valuesof22.6min(mouse),45.7min(rat),67.6min(dog),32.5min(monkey),and34.7min(human),whichisheavilydependentonNADPH[1].PROTACPI3Kαdegrader-1(30-60mg/kg,i.p.,dailyfor14days)demonstratessignificantanticancerefficacyintheHGC-27xenograftmodel[1].PROTACPI3Kαdegrader-1(30mg/kg,i.p.,dailyfor21days)exhibitspotentantitumoractivityintheDOHH2xenograftmodel[1].AnimalModel:MaleBALB/cnudemice(20-22g)bearingHGC-27xenografts[1]2/3 MasterofBioactiveMolecules—您身边的抑制剂大师www.MedChemEDosage:30,60mg/kgAdministration:i.p.dailyfor14daysResult:Showedtumorgrowthrates(TGI)of38.3%at30mg/kgand56.8%at60mg/kg.Induceddose-dependentdegradationofPI3Kα.Showednosignificantchangesinbodyweight.AnimalModel:MaleBALB/cnudemice(20-22g)bearingDOHH2xenografts[1]Dosage:30mg/kgAdministration:i.p.dailyfor21daysResult:Demonstratedastrongefficacywithatumorgrowthinhibition(TGI)rateof61.8%,whichismoreeffectivethanIbrutinib(HY-10997)administeredorallyatadoseof25mg/kgandIdelalisib(HY-13026)administeredorallyatadoseof10mg/kg.Showednosignificantbodyweightloss.REFERENCESPengS,etal.DiscoveryandOptimizationofPotentPROTACDegradersofPhosphoinositide3-KinasewithSignificantinVivoAnticancerEfficacy.JMedChem.2025Jun26;68(12):12800-12818.M