Bromodomain inhibitors revisited Bromodomain and extraterminal domain (BET) proteins contribute to the pathogenesis of cancer and immune diseases through their effects on transcriptional regulation. BET proteins contain two nearly identical bromodomains, BD1 and BD2, structural modules that have attracted great interest as targets for drug development. First-generation drugs that inhibited both BD1 and BD2 showed promising therapeutic activity in preclinical models but proved to be less efficacious in clinical trials. Gilan et al. took a different approach and designed drugs that selectively inhibited BD1 or BD2 (see the Perspective by Filippakopoulos and Knapp). They found that BD1 and BD2 inhibitors altered gene expression in different ways and that BD2 inhibitors had greater therapeutic activity than BD1 inhibitors in preclinical models of inflammation and autoimmune disease. Science, this issue p. 387; see also p. 367 Bromodomain inhibitors, a promising class of epigenetic drugs, are redesigned to enhance their therapeutic efficacy. The two tandem bromodomains of the BET (bromodomain and extraterminal domain) proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models, whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET-targeted therapies.

中文翻译：

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BET 蛋白的 BD1 和 BD2 在癌症和免疫炎症中的选择性靶向


布罗莫结构域抑制剂重新审视布罗莫结构域和末端外结构域 (BET) 蛋白通过对转录调节的影响，促进癌症和免疫疾病的发病机制。 BET 蛋白含有两个几乎相同的溴结构域 BD1 和 BD2，这两种结构模块作为药物开发的靶点引起了人们的极大兴趣。同时抑制 BD1 和 BD2 的第一代药物在临床前模型中显示出有希望的治疗活性，但在临床试验中被证明效果较差。吉兰等人。采用不同的方法并设计了选择性抑制 BD1 或 BD2 的药物（参见 Filippakopoulos 和 Knapp 的观点）。他们发现BD1和BD2抑制剂以不同的方式改变基因表达，并且在炎症和自身免疫性疾病的临床前模型中BD2抑制剂比BD1抑制剂具有更强的治疗活性。科学，本期第 14 页。 387；另见 p. 367 Bromodomain 抑制剂是一类有前途的表观遗传药物，经过重新设计以增强其治疗功效。 BET 蛋白的两个串联溴结构域（溴结构域和末端外结构域）使染色质结合能够促进转录。同样抑制两种溴结构域的药物在某些恶性和炎症性疾病中显示出疗效。为了探索第一溴结构域 (BD1) 和第二溴结构域 (BD2) 在生物学和治疗中的各自功能贡献，我们开发了选择性 BD1 和 BD2 抑制剂。我们发现稳态基因表达主要需要BD1，而炎症刺激诱导的基因表达快速增加需要所有BET蛋白的BD1和BD2。 BD1 抑制剂在癌症模型中模仿了泛 BET 抑制剂的作用，而 BD2 抑制剂主要在炎症和自身免疫性疾病模型中有效。这些对 BD1 和 BD2 在维持和诱导基因表达方面的不同需求的见解可能会指导未来的 BET 靶向治疗。