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研究实现对前列腺癌中BET蛋白BD2溴结构域的选择性抑制
2020-01-29 16:29

美国艾伯维公司Yu Shen团队实现对前列腺癌中BET蛋白BD2溴结构域的选择性抑制。该研究2020年1月22日在线发表于国际一流学术期刊《自然》。

据研究人员介绍,BET(bromodomain and extra-terminal)结构域家族的蛋白质是表观遗传阅读器,它们通过其溴结构域结合乙酰化组蛋白来调节基因转录。在单疗法癌症试验中,与BRD2、BRD3、BRD4和BRDt的第一个(BD1)和第二个(BD2)溴结构域具有相似亲和力的双溴结构域BET抑制剂(DbBi)具有适度的临床活性。对于某些类型的DbBi,血液中血小板数量减少(血小板减少)以及胃肠道毒性症状是限制剂量的不良事件。鉴于在小鼠中Brd4基因沉默后观察到相似的血液学和胃肠道缺陷,血小板和胃肠道毒性可能代表与BET抑制相关的靶标活性。BET家族蛋白中两个单独的溴结构域可能具有不同的功能,并且已经报道了对一个或两个溴结构域的药理抑制作用后,细胞表型也有所不同。这表明与DbBi相比,选择性靶向其中一个溴结构域可能导致不同的功效和耐受性。对单个结构域具有选择性的可用化合物缺乏体内功效和耐受性评估所需的足够效力和药代动力学特性。
 
研究人员进行了一项药物化学研究并发现了ABBV-744,这是一种具有药物样特性的BET家族蛋白BD2结构域的高效选择性抑制剂。与DbBi诱导的广泛的细胞生长抑制相反,ABBV-744的抗增殖活性主要但不限于限于表达全长雄激素受体(AR)的急性髓细胞性白血病和前列腺癌的细胞系。与DbBi ABBV-07514相比,ABBV-744在前列腺癌异种移植物中保留了强大的活性,并显示出更少的血小板和胃肠道毒性。分析RNA表达和染色质免疫沉淀测序,发现ABBV-744将BRD4从含AR的超级增强子中置换出来,并抑制了AR依赖性转录,与ABBV-075相比,对全局转录的影响较小。这些结果强调了选择性靶向BET家族蛋白的BD2结构域用于癌症治疗的潜在价值。

附:英文原文

Title: Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer

Author: Emily J. Faivre, Keith F. McDaniel, Daniel H. Albert, Srinivasa R. Mantena, Joshua P. Plotnik, Denise Wilcox, Lu Zhang, Mai H. Bui, George S. Sheppard, Le Wang, Vasudha Sehgal, Xiaoyu Lin, Xiaoli Huang, Xin Lu, Tamar Uziel, Paul Hessler, Lloyd T. Lam, Richard J. Bellin, Gaurav Mehta, Steve Fidanze, John K. Pratt, Dachun Liu, Lisa A. Hasvold, Chaohong Sun, Sanjay C. Panchal, John J. Nicolette, Stacey L. Fossey, Chang H. Park, Kenton Longenecker, Lance Bigelow, Maricel Torrent, Saul H. Rosenberg, Warren M. Kati, Yu Shen

Issue&Volume: 2020-01-22

Abstract: Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi1,2,3,4,5. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice6, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions7,8,9 and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported10,11, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment10,11,12,13. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-07514. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.

DOI: 10.1038/s41586-020-1930-8

Source: https://www.nature.com/articles/s41586-020-1930-8

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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