Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
West China School of Pharmacy, Sichuan University, Chengdu, 610041, Sichuan, China.
Eur J Med Chem. 2022 Aug 5;238:114419. doi: 10.1016/j.ejmech.2022.114419. Epub 2022 Apr 30.
EZH2, the catalytic subunit of PRC2, catalyzes histone H3 lysine 27 (H3K27) trimethylation to induce the agglutination of chromosomes and in turn represses the transcription of the target genes. Numerous reports indicate that EZH2 is overexpressed in a variety of malignant tumor tissues. Therefore, targeting EZH2 protein is a promising strategy for cancer treatment. So far, many small molecule EZH2 specific inhibitors have entered clinical trials, but many of them harbored limited clinical efficacy. New technologies and methods are imperative to enhance the anticancer activity of EZH2. In this review, the structure and biological functions of EZH2 protein will be reviewed. The internal relationship between EZH2 and various diseases will be expounded. The development status of specific inhibitors for EZH2, and the latest progress of new strategies such as drug combination, dual-target inhibitors, targeted protein degradation technology and protein-protein interactions (PPI) inhibitors will be emphatically summarized and analyzed.
EZH2 是 PRC2 的催化亚基，可催化组蛋白 H3 赖氨酸 27（H3K27）三甲基化，导致染色体凝集，从而抑制靶基因的转录。大量研究表明，EZH2 在多种恶性肿瘤组织中过表达。因此，靶向 EZH2 蛋白是癌症治疗的一种有前途的策略。到目前为止，许多小分子 EZH2 特异性抑制剂已进入临床试验，但其中许多抑制剂的临床疗效有限。为了提高 EZH2 的抗癌活性，新技术和新方法势在必行。在本文中，将对 EZH2 蛋白的结构和生物学功能进行综述，阐述 EZH2 与各种疾病之间的内在关系，重点总结和分析 EZH2 特异性抑制剂的发展现状，以及药物联合、双靶抑制剂、靶向蛋白降解技术和蛋白-蛋白相互作用（PPI）抑制剂等新策略的最新进展。
