Wang Cong, Lu Huasong, Liu Xiangzhong, Gao Xiang, Tian Wenjing, Chen Haifeng, Xue Yuhua, Zhou Qiang
State Key Laboratory of Cellular Stress Biology Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China.
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
iScience. 2021 Dec 31;25(1):103719. doi: 10.1016/j.isci.2021.103719. eCollection 2022 Jan 21.
The BET-bromodomain protein BRD4 uses two bromodomains to target acetyl-histones and other domains to recruit P-TEFb and other transcription factors to stimulate transcription of proto-oncogenes and key cell identity genes. Recent studies show that its ability to form phase-separated condensates that cluster preferentially at the super-enhancer regions of target genes is key for BRD4 to exert its functions. Here, we describe the identification of a natural product called PCG from Sieb.et Zucc., a traditional Chinese medicinal herb, that directly binds to BRD4. This binding inhibits BRD4 phase separation, turns dynamic BRD4 nuclear condensates into static aggregates, and effectively shuts down transcription of BRD4-dependent genes. Thus, through PCG we have discovered a BET inhibitor that not only selectively targets BRD4 but also works by suppressing phase separation, a mechanism of action that is different from those of the other known BET inhibitors.
BET 溴结构域蛋白 BRD4 利用两个溴结构域靶向乙酰化组蛋白及其他结构域，招募 P-TEFb 和其他转录因子，以刺激原癌基因和关键细胞身份基因的转录。最近的研究表明，它形成相分离凝聚物并优先聚集在靶基因超级增强子区域的能力，是 BRD4 发挥其功能的关键。在此，我们描述了从传统中草药浙贝母中鉴定出一种名为 PCG 的天然产物，它能直接与 BRD4 结合。这种结合抑制了 BRD4 的相分离，将动态的 BRD4 核凝聚物转变为静态聚集体，并有效关闭了 BRD4 依赖性基因的转录。因此，通过 PCG，我们发现了一种 BET 抑制剂，它不仅能选择性地靶向 BRD4，而且其作用机制是通过抑制相分离，这与其他已知 BET 抑制剂的作用机制不同。
