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《The PARP Inhibitor AZD2461 Provides InsightsPARPinto the Role of PARP3 Inhibition for BothChemotherapy in Preclinical Models抑制剂AZD2461提供了见解 对PARP3的抑制作用 合成致死性和耐受性 临床前化疗》由会员上传分享,免费在线阅读,更多相关内容在学术论文-天天文库。
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,thefirstPARPinhibitorapprovedPARP3inhibitoryactivityforeachcompoundandahigherforcancertherapy.InBRCA1-deficientmousemodels,olapariblevelofPARP3expressioninbonemarrowcellsfrommiceasresistance
4、predominantlyinvolvesoverexpressionofP-glycopro-comparedwithratsandhumans.Ourfindingshaveimplica-tein,soAZD2461wasdevelopedasapoorsubstratefordrugtionsfortheuseofmousemodelstoassessbonemarrowtransporters.HerewedemonstratetheefficacyofthiscompoundtoxicityforDNA-damagingagentsandinhibitorsoftheDNAa
5、gainstolaparib-resistanttumorsthatoverexpressP-glycoprotein.damageresponse.Finally,structuralmodelingofthePARP3-Inaddition,AZD2461wasbettertoleratedincombinationwithactivesitewithdifferentPARPinhibitorsalsohighlightsthechemotherapythanolaparibinmice,whichsuggeststhatpotentialtodevelopcompoundsw
6、ithdifferentPARPfamilyAZD2461couldhavesignificantadvantagesoverolaparibinthememberspecificityprofilesforoptimalantitumoractivityandclinic.However,thissuperiortoxicityprofiledidnotextendtotolerability.CancerRes;76(20);6084–94.Ó2016AACR.IntroductionPARPinbreastcancerassociated(BRCA)-deficientgeneticba
7、ck-groundsthatareassociatedwithahighlifetimeriskofbreastandInhibitorsoftheDNAdamageresponse(DDR)offeranexcitingovariancancer(5,6).opportunitytoidentifytargetedcancertherapies(1–3).Inaddi-Themechanismforthissingle-agentactivityhasb