Hotline:400-820-3792Inhibitors ? ScreeningLibraries ? Proteinswww.MedChemEMXC-017Cat.No.:HY-174212CASNo.:3037024-97-5分子式:C??H??N?O?S分子量:397.49作用靶點:Apoptosis作用通路:Apoptosis儲存方式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY生物活性MXC-017是一種可穿透血腦屏障(BBB)的凋亡誘導劑，可直接靶向Vimentin(VIM)。MXC-017可阻止放射誘導的膠質(zhì)瘤干細胞(GSC)形成，同時促進G0/G1細胞周期阻滯和細胞凋亡(apoptosis)。MXC-017具有極小的脫靶效應，且無顯著的細胞毒性。MXC-017與放射療法聯(lián)用可顯著延長膠質(zhì)母細胞瘤(GBM)小鼠模型的中位生存期。體外研究MXC-017(1-10μM,5-7days)displaysnoradiosensitizingeffect,butpreventsradiation-inducedinductionofmarker-positivecells,anddose-dependentlyreducessphereformationinHK-374,HK-345andHK-157cellswithaccelerationofGSCexhaustioninHK-374andHK-217cellsat10μM[1].MXC-017(1-10μM,10days)significantlyreducesGSCfrequenciesaloneorcombinationwithradiationinHK-374,HK-390,HK-217,HK-146,HK-308andHK-345cells[1].MXC-017(10μM,2-5days)increasestheradiation-inducedG0/G1arrestwithreductionnumberofcellsinSphase,andsignificantlyincreasestheproportionofapoptoticcellsafter4GyirradiationinHK-374cells[1].MXC-017(10μM,0.25-24h)bindstovimentinandpreventsdecompactionofvimentinintermediatefilaments,withnoproteinlevelschangeintotalvimentinandphosphorylationofSer39,Ser56,orSer83inHK-374cells[1].MXC-017(10μM,6-24h)reducesdetectablebaselinelevelsofvimentinandpreventestheradiationinducedincreaseofthevimentinsignal,whilenochangeintotalvimentinlevelsinHK-374cells[1].MXC-017(10μM,16-24h)significantlysuppressesthemigratorycapacityofHK-374cellwithcombinationofradiationinanindependentmanner[1].MXC-017(10μM,48h)hasnooff-targeteffectswithnometabolicmodulationchanges,butinduces357differentiallyexpressedgenes(239up,118down),enrichingKRASactivation(pro-inflammatoryresponse)andsuppressingE2F/G2Mcheckpoint,withoutcellularcompositionchangesinHK-374,HK-390,HK-2171/4 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemEandHK-244cells[1].MXC-017(1-10μM,24h)causesnosignificanttoxicityinNSPcells(upto2.5μM),NIH3T3andEOC20cells(upto10μM),butsignificantdecreasesplatingefficacyinnormalhumanastrocytes[1].CellMigrationAssay[1]CellLine:HK-374cellsConcentration:10μM,withorwithoutasingledoseof4GyirradiationIncubationTime:16-24hResult:SignificantlyreducedthemigratorycapacityofGBMcellswithlittlecellspenetratingthroughthemembrane.DisplayedMarkedlyimpairedmigrationcomparedtountreatedorradiation-onlycontrols.CellCycleAnalysis[1]CellLine:HK-374cellsConcentration:10μM,withorwithoutasingledoseof4GyirradiationIncubationTime:2or5daysResult:Enhancedtheradiation-inducedG0/G1arrestandreducedthenumberofcellsinSphaseafter4Gyirradiation.ApoptosisAnalysis[1]CellLine:HK-374cellsConcentration:10μM,withorwithoutasingledoseof4GyirradiationIncubationTime:72hResult:Didnotinduceapoptosiswith4Gyirradiationortreatmentalone.Significantlyreducedtheviablecellpopulationandincreasedtheproportionofapoptoticcellsincombinationwith4Gyirradiation.WesternBlotAnalysis[1]CellLine:HK-374cellsConcentration:10μMIncubationTime:0.25,0.5,1,2,4,6,24hResult:DidnotchangetheproteinlevelsoftotalvimentinorphosphorylationofSer39,Ser56,orSer83byusingapolyclonalantibody.2/4 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemE體內(nèi)研究MXC-017(50mg/kg,i.p.,5-dayson/2-daysofffor2weeks,4or10Gyirradiation)significantlyprolongsthemediansurvival,andeffectivelyeliminatesimplantedHK-374cellswithminimaldamagetonormalbraintissueinPDOXGBMmicemodel[1].MXC-017(150-900mg/kg,i.p.,onceor5consecutivedaysperweekfor2weeks)causeamaximumtolerateddoseof150mg/kgwithoutclinicalsignsoftoxicityandsignificanthematologicalorbiochemicalabnormalitiesinC57BL/6micemodel[1].MXC-017(150mg/kg,i.p.,5-dayson/2-daysofffor＞140days)significantlyreducestheprobabilityfortumorrelateddeathinPDOXGBMmicemodelwithcombinationofradiation[1].AnimalModel:FemaleandmaleNSGmice(6-8weeksold)wereimplantedintotherightstriatumofthebrainswithHK-374cells(2?×?105cells/mouse)[1].Dosage:50mg/kgorirradiation(4or10Gy)Administration:i.p.,5-dayson/2-daysofffor2weeksafterimplantingHK-374cells3days,andthencollectedbrainandtumorssamples.Result:ReducedthenumberofspheresformationandsignificantlydecreasedtheGSCfrequencybyMXC-017treatmentaloneandincombinationwith4Gyradiation.Significantlyincreasedthemediansurvivalfrom34to60daysinPDOXGBMmicemodelwithcombinationof10Gyradiation.EffectivelyeliminatedimplantedHK-374cellsincombinationwith10Gyradiation.Causedtumor-freeinlong-termsurvivingPDOXGBMmiceatthetimeofeuthanasiaincombinationwith10Gyradiation.DidnotchangetheproportionsofthecelltypesinPDOXGBMmicemodel.Effectivelyeliminatednestin-positivehumantumorcellswithoutlossofolig2-positiveoligodendrocytesinthecontralateral(non-tumor-bearing)hemisphereincombinationwith10Gyradiation.AnimalModel:FemaleandmaleC57BL/6mice(6-8weeksold)[1].Dosage:Onceadministration(150,300,600,and900mg/kg),repeatedadministration(150,300,600mg/kg)Administration:i.p.,onceinpairs(1male/1female)or5consecutivedaysperweekingroups(3male/3female)for2weeks.Result:Causednosignsoftoxicitywithonceadministrationupto900mg/kg.Causednoclinicalsignsoftoxicityandnosignificanthematologicalorbiochemicalabnormalitieswithrepeatedadministrationupto600mg/kg.Causedmildtoxicitywithperivascularinflammationandsuperficialvasculitisat150mg/kgandacutepneumoniaat600mg/kginthelungswithrepeatedadministration.Causedfocalinterstitialinflammationinthekidneycortexat300mg/kgwithrepeatedadministration.3/4 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemECausedfocallobularinflammationandhepatocellularnecrosisinliverat600mg/kgwithrepeatedadministration.AnimalModel:FemaleandmaleNSGmice(6-8weeksold)wereimplantedintotherightstriatumofthebrains