JMV7048-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEJMV7048Cat.No.:HY-162704CASNo.:2871774-88-6分⼦式:C₅₃H₆₄N₈O₇S分⼦量:957.19作⽤靶点:PROTACs作⽤通路:PROTAC储存⽅式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY⽣物活性JMV7048⼀种有效的靶向PXR(PregnaneX受体)的PROTAC降解剂，DC50为379nM。JMV7048通过招募E3CRBN泛素连接酶和26S蛋⽩酶体来诱导PXR蛋⽩的多泛素化和降解。JMV7048通过减少结肠癌⼲细胞中PXR蛋⽩表达，显著提⾼了结肠癌⼲细胞对化疗的敏感性，从⽽显著延缓了体内癌症复发。JMV7048由PXR激动剂JMV6944(HY-162738)，linker(HY-162736)和Thalidomide5-fluoride(HY-W087383)组成(Red:JMV6944;Blue:Thalidomide5-fluorideligand;Black:linker)[1]。IC50&TargetPregnaneXReceptor(PXR)体外研究JMV7048(5µM,24h)inhibitsthegrowthofcancercellsincoloncancer,livercancer,andpancreaticcancercelllines[1].JMV7048(5µM,48h)significantlyreducesthetumorigenicityofCPP1cellsimplantedinnudemice(i.e.,decreasesthefrequencyoftumorinitiationinnudemice)[1].JMV7048(5µM,48h)reducestheabilityofCPP1,CPP14,andCPP19cellstoformspheresundernon-adherentconditions,indicatingthatJMV7048affectstheself-renewalcapabilityofthesecells[1].JMV7048(5µM,48h)treatmentsignificantlydecreasesthesurvivalrateofHT29cellsaftertreatmentwithchemotherapydrugs(5-Fluorouracil(HY-90006)andSN38(HY-13704)),suggestingthatJMV7048mayenhancethesensitivityofcellstochemotherapydrugs[1].WesternBlotAnalysis[1]CellLine:LS174Tcells(humancolonadenocarcinoma);HepG2(humanhepatoma);AsPC-1(humanmetastaticpancreaticadenocarcinoma),HumanhepatocytesConcentration:0-5000nM,5μM1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEIncubationTime:24h(0-5000nM),0-6h(5μM)Result:PotentlyandefficientlyreducedendogenousPXRproteininLS174Tcells(0-5000nM,24hor5μM,0-6h).SignificantlyreducedtheexpressionofPXRinHepG2cellsandAsPC-1cells(atthedoseof5μM,24h).FailedtodegradePXRinprimaryculturesofhumanhepatocytes(atthedoseof5μM,24h).CellViabilityAssay[1]CellLine:LS174Tcells,HT29cells,CPP1cells,CPP14cells,CPP19cells,CRC1cellsConcentration:0-20µMIncubationTime:72hResult:Resultedinnosignificantchangeincellviabilityafter72hoursoftreatmentatconcentrationsashighas20μM,comparedtotreatmentwiththeactivemetaboliteofirinotecan(HY-16562)(SN38(HY-13704)).体内研究JMV7048(25mg/kg,i.v.,oncedaily,5daysaweek,foratotalof15days)iswelltoleratedinathymicnudemiceandNOD/scidmice[1].JMV7048(25mg/kg,i.v.,oncedaily,for4daysor5daysaweekfor2weeks)showsPXRdegradationactivityinHT29andCCP1-derivedNOD/scidmousexenografttumormodels[1].ThecombinationofJMV7048(25mg/kg,i.v.,oncedaily,5daysaweek,for4weeks(HT29cells);25mg/kg,i.p.,twicedaily,5daysaweek,for3weeks(CCP1cells))withchemotherapy(50mg/kg5-Fluorouracil(HY-90006)+25mg/kgIrinotecan(HY-16562),i.p.,twiceaweek,for3or4weeks)significantlydelaystumorrelapseinNOD/scidmousexenograft(LS174Tcells)models[1].Asinglei.p.injection(50mg/kg)ori.v.injection(25mg/kg)achievesadequatedrugexposurelevelsinplasma,whileoralgavage(50mg/kg)deliveryissignificantlylesseffective[1].PharmacokineticAnalysisinmice[1]JMV7048AUC(μg/L*h)Tmax(min)Cmax(μg/mL)i.v.(25mg/kg)5.19515.4i.p.(30mg/kg)10.55302p.o.(25mg/kg)0.07300.02AnimalModel:HT29andCCP1-derivedxenografttumormodelsinNOD/scidmiceDosage:25mg/kgAdministration:Intraperitonealinjection(i.p.),Intravenousinjection(i.v.),5daysaweekResult:Significantlydelayedtumorrelapseandextendedtumorvolumedoublingtime.AnimalModel:HT29andCCP1-DerivedXenograftTumorModelsinNOD/scidMiceDosage:25mg/kgAdministration:Intravenousinjection(i.v.),oncedailyfor4daysor5daysaweekfor2weeks2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEResult:significantlyreduced(approximately50%)theexpressionofPXRinxenografttumors,suggestingthatJMV7048maintainsPXR-degradingactivityinvivo.REFERENCES[1].BansardL,etal.Apotentagonist-basedPROTACtargetingPregnaneXReceptorthatdelayscoloncancerrelapse[J].202