研究實現對前列腺癌中BET蛋白BD2溴結構域的選擇性抑制
作者：
小柯機器人發布時間：2020/1/29 16:29:30
美國艾伯維公司Yu Shen團隊實現對前列腺癌中BET蛋白BD2溴結構域的選擇性抑制。該研究2020年1月22日在線發表於國際一流學術期刊《自然》。
據研究人員介紹，BET（bromodomain and extra-terminal）結構域家族的蛋白質是表觀遺傳閱讀器，它們通過其溴結構域結合乙醯化組蛋白來調節基因轉錄。在單療法癌症試驗中，與BRD2、BRD3、BRD4和BRDt的第一個（BD1）和第二個（BD2）溴結構域具有相似親和力的雙溴結構域BET抑制劑（DbBi）具有適度的臨床活性。對於某些類型的DbBi，血液中血小板數量減少（血小板減少）以及胃腸道毒性症狀是限制劑量的不良事件。鑑於在小鼠中Brd4基因沉默後觀察到相似的血液學和胃腸道缺陷，血小板和胃腸道毒性可能代表與BET抑制相關的靶標活性。BET家族蛋白中兩個單獨的溴結構域可能具有不同的功能，並且已經報導了對一個或兩個溴結構域的藥理抑制作用後，細胞表型也有所不同。這表明與DbBi相比，選擇性靶向其中一個溴結構域可能導致不同的功效和耐受性。對單個結構域具有選擇性的可用化合物缺乏體內功效和耐受性評估所需的足夠效力和藥代動力學特性。
研究人員進行了一項藥物化學研究並發現了ABBV-744，這是一種具有藥物樣特性的BET家族蛋白BD2結構域的高效選擇性抑制劑。與DbBi誘導的廣泛的細胞生長抑制相反，ABBV-744的抗增殖活性主要但不限於限於表達全長雄激素受體（AR）的急性髓細胞性白血病和前列腺癌的細胞系。與DbBi ABBV-07514相比，ABBV-744在前列腺癌異種移植物中保留了強大的活性，並顯示出更少的血小板和胃腸道毒性。分析RNA表達和染色質免疫沉澱測序，發現ABBV-744將BRD4從含AR的超級增強子中置換出來，並抑制了AR依賴性轉錄，與ABBV-075相比，對全局轉錄的影響較小。這些結果強調了選擇性靶向BET家族蛋白的BD2結構域用於癌症治療的潛在價值。
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