Guo Xuejiao Shirley, Khalifa Abdalrahman, Selvam Karthik, Kutateladze Tatiana G, Liu Wenshe Ray
Texas A&M Drug Discovery Center and Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States.
Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado 80045, United States.
ACS Chem Biol. 2025 Aug 15;20(8):1828-1840. doi: 10.1021/acschembio.5c00349. Epub 2025 Jul 11.
The YEATS domain is an evolutionarily conserved epigenetic reader that specifically recognizes post-translational lysine acylation on histone tails and plays a crucial role in chromatin remodeling and transcriptional regulation. Four human YEATS domain-containing proteins, ENL, AF9, YEATS2, and GAS41, have been implicated in the pathogenesis of various malignancies. This review provides an overview of the structural basis for the YEATS domain's recognition of diverse acyllysine post-translational modifications and discusses the disease-related consequences of aberrant YEATS activity. Emphasis is placed on recent progress in the development of chemical modulators, including peptide-based inhibitors, small molecules, and proteolysis-targeting chimeras (PROTACs), that represent promising strategies for the selective targeting of YEATS domains. These developments underscore the potential of YEATS-directed therapies in epigenetic drug discovery.
YEATS结构域是一种进化上保守的表观遗传阅读器，它能特异性识别组蛋白尾部翻译后赖氨酸酰化，并在染色质重塑和转录调控中发挥关键作用。四种含人类YEATS结构域的蛋白，即ENL、AF9、YEATS2和GAS41，与多种恶性肿瘤的发病机制有关。本综述概述了YEATS结构域识别多种酰基赖氨酸翻译后修饰的结构基础，并讨论了YEATS活性异常与疾病相关的后果。重点介绍了化学调节剂开发方面的最新进展，包括基于肽的抑制剂、小分子和靶向蛋白降解嵌合体（PROTAC），这些代表了选择性靶向YEATS结构域的有前景的策略。这些进展突显了YEATS导向疗法在表观遗传药物发现中的潜力。
