Hotline:400-820-3792Inhibitors ? ScreeningLibraries ? Proteinswww.MedChemEPARP1-IN-40Cat.No.:HY-174442分子式: C??H??FN?O?分子量: 445.49作用靶點(diǎn): PARP作用通路: CellCycle/DNADamage;Epigenetics儲(chǔ)存方式: PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY生物活性PARP1-IN-40是一種具有高度選擇性的具有口服活性的PARP1抑制劑(IC50:PARP1為0.19nM，PARP2為26nM)。PARP1-IN-40通過(guò)抑制PARP1導(dǎo)致DNA損傷累積，殺死腫瘤細(xì)胞。PARP1-IN-40對(duì)BRCA突變的MDA-MB-436細(xì)胞具有較高的抗腫瘤活性。PARP1-IN-40可以與化療聯(lián)合用于癌癥的相關(guān)研究[1]。體外研究PARP1-IN-40(Compound(S)-G9)(1-100nM,3days)blockstheMDA-MB-436cellcycleattheG2/Mphaseandinhibitsproliferation[1].PARP1-IN-40(0.1-1000nM,3days)inducesDNAdamageanddouble-strandbreaksinMDA-MB-436cells[1].PARP1-IN-40(0.1-10000nM,1h)wasalmostinactiveinPARP1-KOcellsinA549cells(IC50>9.8μM),provingthatitsactioniscompletelydependentonPARP1anditsinhibitoryactivityonPARP2isextremelyweak,thusavoidingthetoxicityriskoftraditionalPARPi[1].PARP1-IN-40(0.1-10000nM,1h)efficientlycapturesPARP1-DNAcomplexes(EC50=1.9nM),whilecapturingPARP2requiresathousand-foldconcentration,makingitaPARP1selectivecaptureagent[1].PARP1-IN-40(0.1-20000nM,10days)selectivelykillsBRCAmutantcells,confirmingthatitssyntheticlethalitymechanismdependsonhomologousrecombinationdeficiency[1].CellCycleAnalysis[1]CellLine:MDA-MB-436cellsConcentration:1nM,10nM,100nMIncubationTime:3daysResult:ReducedthenumberofcellsinSphaseandsignificantlyincreasedthenumberofcells1/3 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemEinG2/Mphaseinadose-dependentmanner.CellProliferationAssay[1]CellLine:MDA-MB-436cells,DLD-1BRCA2-KOcells,DLD-1WTcellsConcentration:0.1nM,1nM,10nM,100nM(MDA-MB-436cells,DLD-1BRCA2-KOcells);2.5μM,5μM,10μM,20μM(DLD-1WTcells)IncubationTime:10daysResult:CompletelyinhibitedcloneformationinBRCA1mutant(MDA-MB-436)andBRCA2null(DLD-1KO)cellsatlowconcentrations,andshowednotoxicitytoBRCAwild-typecells(DLD-1WT)evenathighconcentrations.Immunofluorescence[1]CellLine:MDA-MB-436cellsConcentration:0.1nM,1nM,10nM,100nM,1000nMIncubationTime:3daysResult:SignificantlyincreasedthenumberofγH2AXfoci.WesternBlotAnalysis[1]CellLine:MDA-MB-436cellsConcentration:0.1nM,1nM,10nM,100nM,1000nMIncubationTime:3daysResult:IncreasedtheexpressionofγH2AX.體內(nèi)研究PARP1-IN-40(Compound(S)-G9)(0.3-3mg/kg,p.o,for27days)potentlyinhibitsthegrowthofBRCAmutanttumorswithoutsignificanttoxicityintheMDA-MB-231xenograftmicemodel[1].PARP1-IN-40(1-3mg/kg,p.o,for14days)hassynergisticeffectwithchemotherapyintheHCT116xenograftmicemodel[1].PARP1-IN-40(30-300mg/kg,p.o,oncedose;30-100mg/kg,p.o,for14days)ishighlysafeintheBALB/Cnudemice[1].AnimalModel:MDA-MB-231xenograftmodelestablishedinnudemice[1]Dosage:0.3mg/kg,1mg/kg,3mg/kgAdministration:Oraladministration(p.o.),atthecorrespondingdosesfor27days2/3 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemEResult:HadTGIof80%atadoseof0.3mg/kgand94%at3mg/kg,withstablemousebodyweight.BlockedDNArepairintumortissuesbyselectivelyinhibitingPARP1,leadingtotheaccumulationofγH2AX-mediatedDNAdamage,whichinturndownregulatedKi67toinhibitproliferationanddriveanti-tumorefficacy.AnimalModel:HCT116xenograftmodelestablishedinnudemice[1]Dosage:1mg/kgor3mg/kg+liposomalIrinotecan(HY-16562)(2mg/kg)Administration:PARP1-IN-40:Oraladministration(p.o.),atthecorrespondingdosesfor14days;liposomalIrinotecan:Intravenousinjection(i.v.),twiceweeklyfor14days.Result:HadaTGIof80%at1mg/kgcombinedwithchemotherapyand85%at3mg/kg.AnimalModel:FamaleandmaleBALB/Cnudemice[1]Dosage:30mg/kg,100mg/kg,300mg/kgAdministration:Oraladministration(p.o.)at30mg/kgand100mg/kgfor14days;Oraladministration(p.o.)at30mg/kg,100mg/kgand300mg/kgoncedoseResult:Didnotcausedeathorsignificantweightchangesinmice,andthehistologyoftheheart,liver,spleen,lung,andkidneywasnormal.Hadnosignificantorgantoxicityevenatdosesfarhigherthanthetherapeuticdose,andhadexcellentoralsafety.REFERENCESTaoGuo,etal.DiscoveryandPharmacologicalEvaluationofPotentandHighlySelectivePARP1Inhibitors.JMedChem.2025Jul10.68(13)