Qin Ruosong, Ma Baohong, Mou Shuo, Yuan Mengwen, Xing Jiahe, Shen Jiwei, Ding Shi, Chen Ye, Liu Ju
College of Pharmacy of Liaoning University, API Engineering Technology Research Center of Liaoning Province, Small Molecular Targeted Drug R&D Engineering Research Center of Liaoning Province, Shenyang, 110036, Liaoning, People's Republic of China.
School of Pharmacy, North China University of Science and Technology, Tangshan, 063210, Hebei, People's Republic of China.
Mol Divers. 2025 Jul 1. doi: 10.1007/s11030-025-11272-w.
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.
zeste同源物2增强子（EZH2）是多梳抑制复合物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。广泛的研究表明，EZH2在多种恶性肿瘤中经常过度表达，在这些肿瘤中它促进肿瘤发生和进展。EZH2表达升高与肿瘤细胞增殖增加、侵袭、转移、治疗耐药性、更高的肿瘤分级以及不良临床结果密切相关。目前，两种EZH2抑制剂已获得监管批准用于治疗淋巴瘤等癌症，并且两者都已在复发或难治性疾病患者中显示出临床益处。在本综述中，我们对EZH2抑制剂开发的最新进展进行了系统分析，特别强调了基于核心结构支架的分类。我们突出了结构活性关系（SARs）、药理学特性以及临床前开发中代表性化合物各自的优缺点。这些见解旨在为下一代EZH2抑制剂的设计提供参考，以提高其选择性、安全性以及用于靶向癌症治疗的转化潜力。
