Structural characteristics and SARs of EZH2 inhibitors.

IF 3.8 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2025-07-01 DOI:10.1007/s11030-025-11272-w

Ruosong Qin, Baohong Ma, Shuo Mou, Mengwen Yuan, Jiahe Xing, Jiwei Shen, Shi Ding, Ye Chen, Ju Liu

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Abstract

Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the polycomb repressive complex 2 (PRC2), plays a central role in the post-translational methylation of histone H3 lysine 27 (H3K27me3), thereby regulating gene silencing. Extensive studies have demonstrated that EZH2 is frequently overexpressed in a broad range of malignancies, where it promotes tumorigenesis and progression. Elevated EZH2 expression is strongly associated with increased tumor cell proliferation, invasion, metastasis, therapeutic resistance, higher tumor grade, and poor clinical outcomes. Currently, two EZH2 inhibitors have received regulatory approval for the treatment of cancers such as lymphoma, and both have shown clinical benefit in patients with relapsed or refractory disease. In this review, we provided a systematic analysis of recent advances in EZH2 inhibitor development, with a particular emphasis on classification based on core structural scaffolds. We highlighted the structure-activity relationships (SARs), pharmacological profiles, and the respective advantages and limitations of representative compounds in preclinical development. These insights were intended to offer the design of next-generation EZH2 inhibitors with improved selectivity, safety, and translational potential for targeted cancer therapy.

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EZH2抑制剂的结构特征和非典型肺炎。

zeste同源物2增强子（EZH2）是多梳抑制复合体2 （PRC2）的催化亚基，在组蛋白H3赖氨酸27 （H3K27me3）的翻译后甲基化中起核心作用，从而调节基因沉默。大量研究表明，EZH2在广泛的恶性肿瘤中经常过表达，促进肿瘤的发生和进展。EZH2表达升高与肿瘤细胞增殖、侵袭、转移、治疗耐药、肿瘤分级升高和临床预后不良密切相关。目前，两种EZH2抑制剂已获得监管部门批准，用于治疗淋巴瘤等癌症，并且在复发或难治性疾病患者中均显示出临床益处。在这篇综述中，我们系统分析了EZH2抑制剂开发的最新进展，特别强调了基于核心结构支架的分类。我们重点介绍了具有代表性的化合物在临床前开发中的结构-活性关系（SARs）、药理学特征以及各自的优势和局限性。这些见解旨在提供下一代EZH2抑制剂的设计，具有更高的选择性，安全性和靶向癌症治疗的转化潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;