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《The PARP Inhibitor AZD2461 Provides InsightsPARPinto the Role of PARP3 Inhibition for BothChemotherapy in Preclinical Models抑制劑AZD2461提供了見解 對PARP3的抑制作用 合成致死性和耐受性 臨床前化療》由會員上傳分享，免費在線閱讀，更多相關(guān)內(nèi)容在學術(shù)論文-天天文庫。
1、PublishedOnlineFirstAugust22,2016;DOI:10.1158/0008-5472.CAN-15-3240CancerTherapeutics,Targets,andChemicalBiologyResearchThePARPInhibitorAZD2461ProvidesInsightsintotheRoleofPARP3InhibitionforBothSyntheticLethalityandTolerabilitywithChemotherapyinPreclinicalModels1231LenkaOplustilO'Connor,StuartL
2、.Rulten,AaronN.Cranston,RajeshOdedra,14,5335HenryBrown,JannekeE.Jaspers,LouiseJones,CharlotteKnights,BastiaanEvers,11445AttillaTing,RobertH.Bradbury,MarinaPajic,SvenRottenberg,JosJonkers,13211DavidRudge,NiallM.B.Martin,KeithW.Caldecott,AlanLau,andMarkJ.O'ConnorAbstractThePARPinhibitorAZD2461was
3、developedasanext-gener-rats.Investigationsofthisdifferencerevealedadifferentialationagentfollowingolaparib,the?rstPARPinhibitorapprovedPARP3inhibitoryactivityforeachcompoundandahigherforcancertherapy.InBRCA1-de?cientmousemodels,olapariblevelofPARP3expressioninbonemarrowcellsfrommiceasresistance
4、predominantlyinvolvesoverexpressionofP-glycopro-comparedwithratsandhumans.Our?ndingshaveimplica-tein,soAZD2461wasdevelopedasapoorsubstratefordrugtionsfortheuseofmousemodelstoassessbonemarrowtransporters.Herewedemonstratetheef?cacyofthiscompoundtoxicityforDNA-damagingagentsandinhibitorsoftheDNAa
5、gainstolaparib-resistanttumorsthatoverexpressP-glycoprotein.damageresponse.Finally,structuralmodelingofthePARP3-Inaddition,AZD2461wasbettertoleratedincombinationwithactivesitewithdifferentPARPinhibitorsalsohighlightsthechemotherapythanolaparibinmice,whichsuggeststhatpotentialtodevelopcompoundsw
6、ithdifferentPARPfamilyAZD2461couldhavesigni?cantadvantagesoverolaparibinthememberspeci?citypro?lesforoptimalantitumoractivityandclinic.However,thissuperiortoxicitypro?ledidnotextendtotolerability.CancerRes;76(20);6084–94.ó2016AACR.IntroductionPARPinbreastcancerassociated(BRCA)-de?cientgeneticba
7、ck-groundsthatareassociatedwithahighlifetimeriskofbreastandInhibitorsoftheDNAdamageresponse(DDR)offeranexcitingovariancancer(5,6).opportunitytoidentifytargetedcancertherapies(1–3).Inaddi-Themechanismforthissingle-agentactivityhasb
