Xiaolei Huang, Yichang Chen, Qin Xiao, Xinci Shang, Yanli Liu
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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 potential 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. Finally, we will also address the challenges and strategies involved in the development of these inhibitors. 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We will also discuss the structural basis for the potency and selectivity of these inhibitors, which will aid in further lead generation and optimization. Finally, we will also address the challenges and strategies involved in the development of these inhibitors. 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引用次数: 0
摘要
组蛋白甲基化阅读域是一种蛋白质模块,可识别特定的组蛋白甲基化标记,如组蛋白上甲基化或未甲基化的赖氨酸或精氨酸残基。这些阅读器蛋白在基因表达、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。这些蛋白的失调与癌症、神经退行性疾病和发育障碍等多种疾病有关。因此,以这些蛋白为靶点的化学抑制剂已成为一种极具吸引力的治疗干预方法,该领域也取得了重大进展。在本综述中,我们将总结针对组蛋白甲基化阅读器(包括 MBT 结构域、染色质结构域、Tudor 结构域、PWWP 结构域、PHD 手指和 WD40 重复结构域)的抑制剂的开发情况。对于每个结构域,我们将简要讨论其识别和生物/生化功能,然后重点讨论针对该结构域的抑制剂的发现,总结大多数抑制剂的特性和潜在应用。我们还将讨论这些抑制剂的效力和选择性的结构基础,这将有助于进一步产生和优化先导物。最后,我们还将讨论开发这些抑制剂所面临的挑战和策略。在这些数据的帮助下,将有助于合理设计和开发新型化学支架以及组蛋白甲基化阅读域的新靶向策略。
Chemical inhibitors targeting histone methylation readers
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 potential 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. Finally, 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.
期刊介绍:
Pharmacology & Therapeutics, in its 20th year, delivers lucid, critical, and authoritative reviews on current pharmacological topics.Articles, commissioned by the editor, follow specific author instructions.This journal maintains its scientific excellence and ranks among the top 10 most cited journals in pharmacology.