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首页> 外文期刊>Science Advances >Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia
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Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia

机译：溴孢菌素对溴结构域的混杂靶向将BET蛋白确定为白血病初级转录反应的主要调节剂

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Bromodomains (BRDs) have emerged as compelling targets for cancer therapy. The development of selective and potent BET (bromo and extra-terminal) inhibitors and their significant activity in diverse tumor models have rapidly translated into clinical studies and have motivated drug development efforts targeting non-BET BRDs. However, the complex multidomain/subunit architecture of BRD protein complexes complicates predictions of the consequences of their pharmacological targeting. To address this issue, we developed a promiscuous BRD inhibitor [bromosporine (BSP)] that broadly targets BRDs (including BETs) with nanomolar affinity, creating a tool for the identification of cellular processes and diseases where BRDs have a regulatory function. As a proof of principle, we studied the effects of BSP on leukemic cell lines known to be sensitive to BET inhibition and found, as expected, strong antiproliferative activity. Comparison of the modulation of transcriptional profiles by BSP after a short exposure to the inhibitor resulted in a BET inhibitor signature but no significant additional changes in transcription that could account for inhibition of other BRDs. Thus, nonselective targeting of BRDs identified BETs, but not other BRDs, as master regulators of context-dependent primary transcription response.
机译：溴结构域（BRD）已成为癌症治疗的引人注目的目标。选择性有效的BET（溴和末端外）抑制剂的开发及其在多种肿瘤模型中的显着活性已迅速转化为临床研究，并激发了针对非BET BRD的药物开发工作。但是，BRD蛋白复合物的复杂多域/亚基结构使对其药理靶向作用的后果的预测变得复杂。为了解决这个问题，我们开发了一种混杂的BRD抑制剂[溴孢菌素（BSP）]，以纳摩尔亲和力广泛靶向BRD（包括BETs），从而为鉴定具有BRD调节功能的细胞过程和疾病提供了一种工具。作为原理的证明，我们研究了BSP对已知对BET抑制敏感的白血病细胞系的作用，并发现了预期的强抗增殖活性。在短时间暴露于抑制剂后，BSP对转录谱调节的调节作用的比较导致了BET抑制剂的作用，但是转录方面没有明显的其他变化，这可以解释为对其他BRD的抑制作用。因此，对BRD的非选择性靶向将BETs（而非其他BRD）鉴定为上下文相关的初级转录反应的主要调控因子。

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