资源描述：
《Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer (1)电子版》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、LETTERdoi:10.1038/nature13229TherapeutictargetingofBETbromodomainproteinsincastration-resistantprostatecancer1,211,21,2131IrfanA.Asangani,VijayaL.Dommeti,XiaojuWang,RohitMalik,MarcinCieslik,RendongYang,JuneEscara-Wilke,411111,21,5KariWilder-Romans,SudheerDhanireddy,CarlEngelke,MathewK.Iyer,Xi
2、aojunJing,Yi-MiWu,XuhongCao,36,71,4,71,2,5,7,8ZhaohuiS.Qin,ShaomengWang,FelixY.Feng&ArulM.ChinnaiyanMenwhodevelopmetastaticcastration-resistantprostatecancer(CRPC)Furthermore,JQ1treatmentinducedG0–G1arrest,apoptosisandassoc-invariablysuccumbtothedisease.ProgressiontoCRPCafterandro-iatedtransc
3、riptionaldownregulationoftheanti-apoptoticproteinBCL-xl13,18genablationtherapyispredominantlydrivenbyderegulatedandrogen(alsoknownasBCL2L1)inAR-positivecells(Fig.1bandExtended1–3receptor(AR)signalling.DespitethesuccessofrecentlyapprovedDataFig.1f–h).SimilartoBCL2downregulationbytheBETinhibito
4、r4–610therapiestargetingARsignalling,suchasabirateroneandsecond-I-BET151inleukaemia,areductioninBCL-xlbyJQ1couldbeexplainedgenerationanti-androgensincludingMDV3100(alsoknownasinpartbytheobservedlossofBRD2/3/4recruitmenttoitspromoter7,8enzalutamide),durableresponsesarelimited,presumablyowingto
5、region(ExtendedDataFig.1j).Evenatarelativelylow100nanomolaracquiredresistance.Recently,JQ1andI-BET762twoselectivesmall-(nM)concentration,long-termcolonyformationofAR-positivecellswasmoleculeinhibitorsthattargettheamino-terminalbromodomainsseverelyinhibitedbyJQ1(ExtendedDataFig.1k)withnoappare
6、nteffectofBRD4,havebeenshowntoexhibitanti-proliferativeeffectsinaonJQ1targetproteins(ExtendedDataFig.1l,m).9–12rangeofmalignancies.HereweshowthatAR-signalling-competentAsAR-positivecellswerepreferentiallysensitivetoJQ1,weexaminedhumanCRPCcelllinesarepreferentiallysensitivetobromodomainwhether
7、JQ1hasaneffectonARtargetgenes.VCaPhumanprostateandextraterminal(BET)inhibition.BRD4physicallyinteractswithcancercellsthatharbourtheTMPRSS2-ERGgenefusionandARamp-20theN-terminaldomainofARandcanbedisruptedbyJQ1(refs11,13).lificationshowedadose-
