Hsp90 molecular chaperone inhibitors Are we there yet.PDF

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1、NeckersandWorkmanPage17Publishedinfinaleditedformas:ClinCancelRes.2012January1;18(1):64—76.doi:10.1158/1078-0432.CCR--1000.ClinCancerRes.Authormanuscript;availableinPMC2012July1•NeckersandWorkmanPage17NIH-PAAuthorManuscriptNIH-PAAuthorManuscriptNIH-bAAuthorManuscriptH

2、sp90molecularchaperoneinhibitors:Arewethereyet?LenNeckers1andPaulWorkman21UrologicOncologyBranch,CenterforCancerResearch,NationalCancerInstitute,9000RockvillePikeBldg.10/CRC,Room1-5940,Bethesda，MD20892-1107USA2SignalTransductionandMolecularPharmacologyTeam，CancerResea

3、rchUKCancerTherapeuticsUnit,DivisionofCancerTherapeutics,TheInstituteofCancerResearch,HaddowLaboratories，15CotswoldRoad,SuttonSM25NGUKAbstractHeatshockprotein(Hsp)90isanATP-dependentmolecularchaperoneexploitedbymalignantcellstosupportactivatedoncoproteins，includingman

4、ycancer-associatedkinasesandtranscriptionfactors，andisessentialforoncogenictransformation.Originallyviewedwithskepticism,Hsp90inhibitorsarenowactivelypursuedbythepharmaceuticalindustry,with17agentshavingenteredclinicaltrials.Hsp90’sdruggabilitywasestablishedusingthena

5、turalproductsgeldanamycinandradicicolwhichmimictheunusualATPstructureadoptedinthechaperone’sN-terminalnucleotide-bindingpocketandcausepotentandselectiveblockadeofATPbinding/hydrolysis，inhibitchaperonefunction，depleteoncogenicclients，anddemonstrateantitumoractivity.Pre

6、clinicaldatawiththesenaturalproductshaveheightenedinterestinHsp90asadrugtarget，and17-allylamino-17-demethoxygeldanamycin(17-AAG，tanespimycin)hasdemonstratedclinicalactivity(asdefinedbyRECISTcriteria)inHER2+breastcancer.ManyoptimizedsyntheticsmallmoleculeHsp90inhibitor

7、sfromdiversechemotypesarenowinclinicaltrials.WereviewthediscoveryanddevelopmentofHsp90inhibitorsandassesstheirfuturepotential.TherehasbeensignificantlearningfromexperienceinboththebasicbiologyandthetranslationaldrugdevelopmentaroundHsp90,enhancedbytheuseofHsp90inhibit

8、orsaschemicalprobes.Successwilllikelylieintreatingcancersaddictedtoparticulardriveroncogeneproducts，suchasHER2,ALK，EGFRandBR