GPX4-IN-19-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors • ScreeningLibraries • Proteinswww.MedChemEGPX4-IN-19Cat.No.:HY-178364CASNo.:3102894-57-2分子式:C₁₉H₁₉ClFNO₅分子量:395.81作用靶点:GlutathionePeroxidase;Ferroptosis;Lipoxygenase;ReactiveOxygenSpecies(ROS);DNA/RNASynthesis作用通路:Apoptosis;MetabolicEnzyme/Protease;Immunology/Inflammation;NF-κB;CellCycle/DNADamage储存方式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY生物活性GPX4-IN-19是一种有效的GPX4抑制剂(IC50=0.311μM)，与GPX4的Sec46位点共价结合。GPX4-IN-19具有很强的抗增殖活性和铁死亡(ferroptosis)高选择性。GPX4-IN-19可导致细胞内Fe²积累，进而导致脂质过氧化物(LPOs)和活性氧(ROS)水平升高，最终诱导铁死亡(ferroptosis)并造成DNA损伤。GPX4-IN-19可用于三阴性乳腺癌(TNBC)的研究[1]。体外研究GPX4-IN-19(CompoundY19)(72h)exhibitseffectiveanti-proliferativeactivitytosixcancercelllines(MCF-7,MDA-MB-231,PC-3,MDA-MB-468,PANC-1,andASPC-1)(IC50:0.021-0.094μM)[1].GPX4-IN-19(12.5-50nM,2weeks)caneffectivelyinhibitcellproliferation,andtheadditionoftheinhibitorFerrostatin-1(HY-100579)(Fer-1)reversedtheinhibitionofcellproliferationinMDA-MB-231cells[1].GPX4-IN-19(50nM,8h)cancausemitochondriainthecellstoshowtypicalmorphologicalchanges,suchasruptureoftheoutermitochondrialmembrane,smallermitochondrialvolume,andreductionorabsenceofinnermitochondrialcristainMDA-MB-231cells[1].GPX4-IN-19(12.5-50nM,8h)inducesdose-dependentincreasesinintracellularFe²concentration,LPOsaccumulation,MDAcontent,andROSlevelinMDA-MB-231cells[1].GPX4-IN-19(12.5-50nM,8h)causesDNAdamageinMDA-MB-231cellsbyincreasingtheexpressionofγH2AX,andthisDNAdamageissignificantlyattenuatedbytheadditionofinhibitorssuchasFer-1[1].GPX4-IN-19(1μM,2h)reducesthedegradationtemperatureofGPX4proteinatthesametemperatureinMDA-MB-231cells,indicatingthatGPX4-IN-19reducedthethermalstabilityofGPX4protein[1].GPX4-IN-19(12.5nM,25nM,50nM,8h)exhibitssignificantresistanceintheMDA-MB-231celllinesthatareresistanttoGPX4inhibitorsRSL3orML162(MDA-MB-231-RSL3andMDA-MB-231-ML162)[1].GPX4-IN-19(12.5-50nM,4-12h)reducesGPX4levelsinaconcentration-dependentmannerinMDA-MB-1/3 MasterofBioactiveMolecules—您身边的抑制剂大师www.MedChemE231cells.However,time-courseanalysisrevealsthatGPX4expressioninitiallyincreasesat4hours,withminimalchangeinxCTlevelsatthisearlytimepoint,butsubsequentlydecreasesat8hoursaccompaniedbyasignificantincreaseinxCTexpression[1].CellProliferationAssay[1]CellLine:MDA-MB-231cellsConcentration:12.5nM,25nM,50nMIncubationTime:2weeksResult:Effectivelyinhibitedcellproliferation,andtheadditionoftheinhibitorFer-1reversedtheinhibitionofcellproliferationinMDA-MB-231cells.WesternBlotAnalysis[1]CellLine:MDA-MB-231cellsConcentration:12.5nM,25nM,50nMIncubationTime:8hResult:IncreasedexpressionofDNAdamagemarkerγH2AX.DecreasedthelevelofGPX4inaconcentration-dependentmanner.Didn'tinhibitotherproteinscontainedselenium,includingGlutathioneperoxidase1(GPX1)andThioredoxinreductase1(TXNRD1).FTH1wassignificantlydecreasedwiththeconcentrationchange.IncreasedACSL4expressionlevels.Immunofluorescence[1]CellLine:MDA-MB-231cellsConcentration:12.5nM,25nM,50nMIncubationTime:8hResult:ReducedGPX4levelinaconcentration-dependentmannerinMDA-MB-231cells.WesternBlotAnalysis[1]CellLine:MDA-MB-231cellsConcentration:12.5nM,25nM,50nMIncubationTime:4h,8h,12hResult:TheexpressionofGPX4increasedat4h,andthexCTleveloftheupstreamsignalingpathwayhardlychangedatthistime,buttheexpressionlevelofGPX4decreasedand2/3 MasterofBioactiveMolecules—您身边的抑制剂大师www.MedChemEtheexpressionlevelofxCTincreasedat8h.体内研究GPX4-IN-19(5mg/kg,10mg/kg,i.p.,everytwodaysfor24days)demonstratesadose-dependentantitumoreffectintheMDA-MB-231tumor-bearingmousemodelwithoutcausingsignificantweightloss,abnormalbloodbiochemicalindicators,ororganpathologicaldamage,showinggoodsafetycharacteristics[1].AnimalModel:MDA-MB-231cells(1×107cellsin200μLsuspension,mixed1:1withMatrigelandPBS)aresubcutaneouslyinjectedintotheleftflankoffemaleBALB/cnudemice(4to5weeksold)[1].Dosage:5mg/kg,10mg/kgAdministration:I.p.,everytwodaysfor24daysResult:Tumorgrowthwasinhibitedinadose-dependentmanner,tumorgrowthinhibition(TGI)of72.53%at10mg/kg.Ki67-positivetumorcellsweredecreased.GPX4wassignificantlydecreasedcomparedwiththecontrolgroup.Revealednoapparentmorphologicalabnormalitiesinmajororgans,includingtheheart,liver,spleen,lungs,andkidneys.Couldnotdestroythefunctionoftheliver,thekidneys,andtheheart.REFERENCESNingM,etal.DiscoveryofnovelbenzylanilinederivativescontainingchloroacetamideasGPX4inhibitorswithpotentialefficacyintriple-negativebreastcancer