Histone methylation reader domains are protein modules that recognize specific histone methylation marks, such as methylated or unmethylated lysine or arginine residues on histones. These reader proteins play crucial roles in the epigenetic regulation of gene expression, chromatin structure, and DNA damage repair. Dysregulation of these proteins has been linked to various diseases, including cancer, neurodegenerative diseases, and developmental disorders. Therefore, targeting these proteins with chemical inhibitors has emerged as an attractive approach for therapeutic intervention, and significant progress has been made in this area. In this review, we will summarize the development of inhibitors targeting histone methylation readers, including MBT domains, chromodomains, Tudor domains, PWWP domains, PHD fingers, and WD40 repeat domains. For each domain, we will briefly discuss its identification and biological/biochemical functions, and then focus on the discovery of inhibitors tailored to target this domain, summarizing the property and penitential application of most inhibitors. We will also discuss the structural basis for the potency and selectivity of these inhibitors, which will aid in further lead generation and optimization. We will also address the challenges and strategies involved in the development of these inhibitors. It should facilitate the rational design and development of novel chemical scaffolds and new targeting strategies for histone methylation reader domains with the help of this body of data.

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针对组蛋白甲基化读取器的化学抑制剂

组蛋白甲基化阅读器结构域是识别特定组蛋白甲基化标记的蛋白质模块，例如组蛋白上的甲基化或未甲基化赖氨酸或精氨酸残基。这些读取蛋白在基因表达、染色质结构和 DNA 损伤修复的表观遗传调控中发挥着至关重要的作用。这些蛋白质的失调与多种疾病有关，包括癌症、神经退行性疾病和发育障碍。因此，用化学抑制剂靶向这些蛋白质已成为治疗干预的一种有吸引力的方法，并且该领域已取得重大进展。在这篇综述中，我们将总结针对组蛋白甲基化读取器的抑制剂的开发，包括 MBT 结构域、染色结构域、Tudor 结构域、PWWP 结构域、PHD Finger 和 WD40 重复结构域。对于每个结构域，我们将简要讨论其识别和生物/生化功能，然后重点关注针对该结构域的抑制剂的发现，总结大多数抑制剂的性质和应用。我们还将讨论这些抑制剂的效力和选择性的结构基础，这将有助于进一步的先导化合物产生和优化。我们还将解决开发这些抑制剂所涉及的挑战和策略。借助这些数据，它应该有助于合理设计和开发新型化学支架以及针对组蛋白甲基化阅读器结构域的新靶向策略。