PARP1-IN-34-生命科學(xué)試劑-MCE

Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEPARP1-IN-34Cat.No.:HY-170432分?式:C??H??N?O?分?量:433.51作?靶點(diǎn):PARP作?通路:CellCycle/DNADamage;Epigenetics儲(chǔ)存?式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY?物活性PARP1-IN-34(compound30)?種PARP1的選擇性抑制劑，IC50為0.32nM。PARP1-IN-34?種亞納爾PARP1抑制劑，對(duì)PARP2的選擇性為1000倍，IC50為326nM。PARP1-IN-34具有抗癌活性。IC50&TargetPARP1PARP20.32nM(IC50)326nM(IC50)體外研究PARP1-IN-34showsthePARP1trappingwithEC50of34.7,65.9,102.7nMat60,120,180min,respectively[1].PARP1-IN-34showsveryweakPARP2trappingwithanEC50of9882nM[1].PARP1-IN-34(180min)formedatighterPARP1-DNAtrappingthanAZD9574[1].PARP1-IN-34(10nM,72h)stimulatesDNAdouble-standsbreaksinMDA-MB-436cells.PARP1-IN-34(10nM,72h)couldincreasethelevelsofγH2AXinMDA-MB-436cellsandcausesmoresignificantDNAdamageincellsthanAZD9574[1].PARP1-IN-34displaysneglectableantiproliferationactivitiesintheseBRCAWTcells(CAL-148,22RV1,andPC3cell)and293Tnormalcells(IC50>10,000nM),incontrasttoIC50=2.6nMinBRCA-mutatedMDA-MB-436cells,whichindicatesthatitscellularactivityisPARP1inhibition-dependent[1].PARP1-IN-34isahighlyselectivePARP1inhibitoroverotherPARPs,includingPARP2,PARP3,PARP5A,PARP5B,PARP6,PARP7,PARP12,PARP14,andPARP15[1].WesternBlotAnalysisCellLine:MDA-MB-436cellsConcentration:10nM1/4MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEIncubationTime:72hResult:IncreasedthelevelsofγH2AXat10nMinMDA-MB-436cellsandcausesmoresignificantDNAdamageincellsthanAZD9574體內(nèi)研究PARP1-IN-34(0.2-0.6mg/kg,p.o.,daily,35days)inducestumorshrinkageinadose-dependentmannerintheMDA-MB-436mousexenograftmodel[1].PARP1-IN-34(10mg/kg,p.o.,daily,35days)hassynergywithCarboplatin(HY-17393)intheSUM149PTxenograftmodel[1].PARP1-IN-34(5,25mg/kg,p.o.,daily,14days)hasminimalimpactonRET(reductionofthereticulocyte)[1].PharmacokineticsofPARP1-IN-34intheMouse,Rat,andDpertymouseratdogplasmaproteinunboundfraction0.0120.0670.022t1/2(h)Vss(L/kg)0.341.420.36CLp(mL/min/kg)2.04.90.58AUC(0-t)(ng·hr/mL)po456881362215024F(%)132.493.167.3TherapeuticIndexofPARP1-IN-34ComparedwithOtherPARPInhibitors.CompoundOlaparibAZD5305AZD9574PARP1-IN-34PotencyPARP1IC50(nM)PARP2IC50(nM)PARP1/2foldselectivity0.950.340.390.4610220.876727720.323261019InvivoefficacyinMDA-MB-436Doseoftumorregression≥50%AUC(ng/mlhr)Unbound%inmiceFree-drugAUC(ng/mlhr)100mg/kg3142629.3%92080.1mg/kg40432%812mg/kg97764%3910.6mg/kg10391.2%12.5HematoxinratDoseofRET>50%↓2/4MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEAUC(ng/mlhr)Unbound%inratFree-drugAUC(ng/mlhr)>100mg/kg3083659.7%29911>25mg/kg1335416.7%8947TherapeuticindexFoldofFree-drugAUC>76.5>715AnimalModel:FemaleBalb/cathymicnudemice(VitalRiver)(6-8weeks)weresubcutaneouslyimplantedwith1×107MDA-MB-436cellsin0.2mLMatrigelsolutionintherightflank[1].Dosage:0.2,0.6mg/kgAdministration:p.o.,daily,35daysResult:At0.6mg/kgQDinducedtumorshrinkageby65.7%,whichwasstrongerthantheefficacyofAZD9574at0.6mg/kgQD(38.1%shrinkage)andthatofAZD5305at0.03mg/kgQD(24.4%shrinkage).Inducedminimalchangesinanimalbodyweight.AnimalModel:FemaleBalb/cathymicnudemice(VitalRiver)(6?8weeks)weresubcutaneouslyimplantedwith1×107SUM149PTcellsin0.2mLMatrigelsolutionintherightflank.[1].Dosage:10mg/kgAdministration:p.o.,daily,35daysResult:Incombinationwithweekly37.5mg/kgcarboplatindemonstratedgreatimprovementoftheantitumoreffectcomparedtocarboplatinmonotherapy(94.7%TGIvs69.7%TGI).Inducednosignificantbodyweightlossduringthestudy.AnimalModel:FemaleBalb/cathymicnudemice(VitalRiver)(6?8weeks)weresubcutaneouslyimplantedwith1×107SUM149PTcellsin0.2mLMatrigelsolutionintherightflank.[1].Dosage:5,25mg/kgAdministration:p.o.,daily,14daysResult:HadminimalimpactonRET(reductionofthereticulocyte).Inducednosignificantbodyweightlossduringthestudy.REFERENCES3/4MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE[1].GaoS,HouY,etal.DiscoveryofPyrazolo[1,5,4-de]quinoxalin-2(3H)-oneDerivativesasHighlyPotentandSelectivePARP1Inhibitors.JMedChem.2024Dec12;67(2