GP262-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEGP262Cat.No.:HY-180261分⼦式:C₅₆H₇₂N₁₂O₈S分⼦量:1073.31作⽤靶点:PROTACs;mTOR;PI3K;Apoptosis作⽤通路:PROTAC;PI3K/Akt/mTOR;Apoptosis储存⽅式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY⽣物活性GP262⼀种靶向PI3Kγ、PI3K和mTOR的PI3K/mTORPROTAC降解剂，在MDA-MB-231细胞中的DC50分别为42.23nM和45.4nM。GP262可诱导p110α和p110γ的降解其DC50分别为42.23nM、227.4nM和45.4nM。GP262在体外表现出显著的抗增殖活性并能诱导细胞凋亡(apoptosis)。GP262⾼效调控PI3K/AKT/mTOR信号通路，并通过泛素-蛋⽩酶体系统实现靶蛋⽩降解。GP262在体内显⽰出抑制肿瘤⽣长的能⼒及良好的⽣物安全性。GP262可⽤于⽩⾎病和三性乳腺癌(TNBC)的研究[1]。IC50&Targetp110αp110γmTOR227.4nM(DC50)42.23nM(ED50)45.4nM(Kd)体外研究GP262(0-5μM,0-24h)efficientlyreducesPI3KandmTORLevelsandthisdegradationisattenuatedupon26Sproteasomeinhibition,canbeblockedunderhighconcentrationcompetition(MG132(HY-13259)andVH032(HY-120217))anddependsonVHLrecruitmentinMDA-MB-231cells[1].GP262(8-1000nM)significantlyinhibitsproliferationandinducesprogrammedcelldeath(apoptosis),revealsdose-dependentgrowthinhibitionwithIC50valuesof68.0nM(inMDA-MB-231),161.6nM(inMCF-7),and124.2nM(inMDA-MB-361),achievingmaximuminhibition(Imax)of65.4,83.4,and97.7%respectively,impairscolonyformationinMDA-MB-231cellsat200nM,andhasadegradationefficacyagainstmTORandPI3KαwithIC50valuesof167.6and40nMinMCF-7cells[1].GP262(8-5000nM,24h)demonstratesconcentration-dependentreductionofPI3KγproteinlevelsinTHP-1cellsandantiproliferativeeffectsinOCI-AML3(IC50=44.3nM)andTHP-1cells(IC50=48.3nM)[1].GP262(1000nM,12h)increasesapoptosisto32.1%inMDA-MB-231cells[1].GP262(0.03125-2μM)revealsdissociationconstantswithKdof0.867μMforPI3Kαand0.479μMformTOR[1].GP262inducespolyubiquitination-dependentproteasomaldegradation[1].1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEGP262exhibitsexcellentkinaseselectivityforthePI3KfamilyandmTOR,therebyinducingwidespreadtranscriptomicalterationsincludingmultipledifferentiallyexpressedgenes(DEGs)associatedwithcellcycleregulation,cancer-relatedprocesses,andapoptosis,whichcollectivelydemonstratesignificantenrichmentandprofoundimpactoncellcycle-relatedpathwaysinMDA-MB-231cells[1].WesternBlotAnalysis[1]CellLine:MDA-MB-231cellsConcentration:8,40,200,1000and5000nMIncubationTime:0,3,6,9,12and24hResult:Induceddegradationofp110αwithaDC50of227.4nMandaDmaxof71.3%.Induceddegradationofp110γwithaDC50of42.23nMandaDmaxof88.6%.InduceddegradationofmTORwithaDC50of45.4nMandaDmaxof74.9%.SignificantlyinhibitedAKTactivation(p-AKT)withoutaffectingthetotalAKTproteinlevels.Reducedp85,p-GSKandp-4EBP1proteinlevel.Inducedtime-dependentproteolysisofmTORandp110αat1μM,exhibitingsignificantdegradationwithin12handmaximalefficiencyby24h,andthiseffectwasmarkedlyattenuatedupon26SproteasomeinhibitionandwasalsoinhibitedbysiRNA-mediatedVHLknockdown(500nM,24h).WesternBlotAnalysis[1]CellLine:THP-1cellsConcentration:8,40,200,1000and5000nMIncubationTime:24hResult:Demonstratedconcentration-dependentreductionofPI3Kγproteinlevels(DC50=88.4nM)with>70%maximaldegradationefficiencyachievedafter24-htreatment.体内研究GP262(15or25mg/kg,i.p.,dailyfor20consecutivedays)effectivereducestargetproteinlevels(PI3KandmTOR)intumortissuesandsignificanttumorgrowthinhibitionandexhibitsexcellentsafetyandtolerabilitywithoutcausingsignificantsystemictoxicityororgandamageinMDAMB-231triple-negativebreastcancerxenograftNOD-SCIDmicemodel[1].AnimalModel:MDAMB-231cellsinduced-femaleNOD-SCIDmice(60-70daysold,22-24g)[1]Dosage:15or25mg/kgAdministration:i.p.,dailyfor20consecutivedaysResult:Showed57.8%tumorgrowthinhibitionat15mg/kgand79.2%tumorgrowthinhibitionat2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemE25mg/kg.Maintainedbodyweightfluctuationswithin10%.ReducedPI3KandmTORproteinexpression.DecreasedexpressionoftheproliferationmarkerKI67.Showednosignificantlyinflammatoryinfiltration,necrosis,orstructuralabnormalitiesinmajororgans(heart,liver,andkidney).REFERENCES[1].ZhuW,etal.DiscoveryoftheFirstPotentPI3K/mTORDual-TargetingPROTACDegraderforEfficientModulationofthePI3K/AKT/mTORPathway.JMedChem.2025Dec25;