PF-543-hydrochloride-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•Agonists•ScreeningLibrariesPF-543hydrochlorideCat.No.:HY-15425BCASNo.:1706522-79-3分⼦式:C₂₇H₃₂ClNO₄S分⼦量:502.07作⽤靶点:SPHK;LPLReceptor;Apoptosis;Autophagy作⽤通路:Immunology/Inflammation;GPCR/GProtein;Apoptosis;Autophagy储存⽅式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY⽣物活性PF-543hydrochloride(SphingosineKinase1InhibitorIIhydrochloride)⼀种有效，选择性，可逆和鞘氨醇竞争性SPHK1抑制剂，IC50为2nM，Ki为3.6nM。PF-543hydrochloride对SPHK1的选择性SPHK2的100倍以上。PF-543hydrochloride还有效的全⾎中1-磷酸鞘氨醇(S1P)形成的有效抑制剂，IC50为26.7nM。PF-543hydrochloride诱导细胞凋亡，坏死和⾃噬。IC50&TargetIC50:2nM(SPHK1);26.7nM(Sphingosine1-phosphate(S1P))[1]Ki:3.6nM(SPHK1)[1]体外研究PF-543(10-1000nM;24ꢀhours;PASMcells)treatmentabolishesSK1expressionatnMconcentrations[2].PF-543(0.1-10μM;24hours;PASMcells)treatmentinducescaspase-3/7activity[2].PF-543inhibitsC17-S1Pformationin1483cellswithanIC50of1.0nM[1].SphK1inhibitionbyPF-543causesadose-dependentdepletionoftheintracellularlevelofS1PwithEC50concentrationof8.4nMandaconcomitantelevationoftheintracellularlevelofsphingosinein1483cells.ThelevelofendogenousS1Pin1483cellsaftera1htreatmentwith200nMPF-543isdecreased10-fold,producingaproportionalincreaseinthelevelofsphingosine[1].WesternBlotAnalysis[2]CellLine:Humanpulmonaryarterialsmoothmuscle(PASM)cellsConcentration:10nM,100nM,1000nMIncubationTime:24ꢀhoursResult:AbolishedSK1expressionatnMconcentrations.1/3ApoptosisAnalysis[2]CellLine:Humanpulmonaryarterialsmoothmuscle(PASM)cellsConcentration:0.1μM,1μM,10μMIncubationTime:24ꢀhoursResult:Inducedcaspase-3/7activityinculturedhumanpulmonarysmoothmusclecells.体内研究PF-543(1mg/kg;intraperitonealinjection;everysecondday;for21days;femaleC57BL/6Jmice)treatmenthasnoeffectonvascularremodellingbutreducesrightventricularhypertrophy.Theprotectioninvolvesareductionintheexpressionofp53andanincreaseintheexpressionofanti-oxidantnuclearfactorNrf-2[2].Miceareinitiallydosed(ip)with10mg/kgor30mg/kgofPF-543for24handtheT1/2is1.2hinbloodsamples.Administrationof10mg/kgPF-543for24htomiceinducesadecreaseinSK1expressioninpulmonaryvessels[2].AnimalModel:FemaleC57BL/6Jmice(7-12week-old)withhypoxic-inducedpulmonaryarterialhypertension[2]Dosage:1mg/kgAdministration:Intraperitonealinjection;everysecondday;for21daysResult:Reducedrightventricularhypertrophy.Theprotectioninvolvesareductionintheexpressionofp53(thatpromotescardiomyocytedeath)andanincreaseintheexpressionofanti-oxidantnuclearfactorNrf-2.REFERENCES[1].SchnuteME,etal.ModulationofcellularS1Plevelswithanovel,potentandspecificinhibitorofsphingosinekinase-1.BiochemJ.2012May15;444(1):79-88.[2].MacRitchieN,etal.Effectofthesphingosinekinase1selectiveinhibitor,PF-543onarterialandcardiacremodellinginahypoxicmodelofpulmonaryarterialhypertension.CellSignal.2016Aug;28(8):946-55.[3].HamadaM,etal.Inductionofautophagybysphingosinekinase1inhibitorPF-543inheadandnecksquamouscellcarcinomacells.CellDeathDiscov.2017Aug14;3:17047