组蛋白
细胞生物学
共价键
生物化学
染色质
组蛋白脱乙酰基酶
化学生物学
作者
Yi Zhang,Deqin Rong,Bingbing Li,Wang Yuanxiang
标识
DOI:10.1021/acs.jmedchem.0c02055
摘要
Epigenetic regulation of gene expression plays a critical role in various physiological processes, and epigenetic dysregulation is implicated in a number of diseases, prominently including cancer. Epigenetic regulators have been validated as potential therapeutic targets, and significant progress has been made in the discovery and development of epigenetic-based inhibitors. However, successful epigenetic drug discovery is still facing challenges, including moderate selectivity, limited efficacy, and acquired drug resistance. Inspired by the advantages of covalent small-molecule inhibitors, targeted covalent inhibition has attracted increasing interest in epigenetic drug discovery. In this review, we comprehensively summarize the structure-based design and characterization of covalent inhibitors targeting epigenetic writers, readers, and erasers and highlight their potential benefits in enhancing selectivity across the enzyme family and improving in vivo efficacy. We also discuss the challenges and opportunities of covalent small-molecule inhibitors and hope to shed light on future epigenetic drug discovery.
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