Xia Juan, Li Jingyi, Tian Lei, Ren Xiaodong, Liu Chang, Liang Chengyuan
Laboratory of Hematologic Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, P. R. China.
Faculty of Pharmacy, Shaanxi University of Science & Technology, Xi'an 710021, P. R. China.
J Med Chem. 2022 May 26;65(10):7016-7043. doi: 10.1021/acs.jmedchem.2c00047. Epub 2022 May 7.
Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that can change the expression of downstream target genes by catalyzing the trimethylation of lysine 27 of histone H3 (H3K27me3). Studies have found that EZH2 is highly expressed in a variety of tumor tissues and is closely related to the occurrence, development, invasion, and metastasis of tumors; therefore, EZH2 is becoming a new molecular target in antitumor therapy. Tazemetostat (EPZ-6438) was approved in 2020 as the first inhibitor targeting catalytic EZH2 for the treatment of epithelioid sarcoma. In addition, a variety of EZH2 inhibitors are being investigated in basic and clinical research for the treatment of tumors, and encouraging results have been obtained. This article systematically reviews the research progress on EZH2 inhibitors and proteolysis targeting chimera (PROTAC)-based EZH2 degradation agents with a focus on their design strategies, structure-activity relationships (SARs), and safety and clinical manifestations.
zeste同源物2增强子（EZH2）是一种组蛋白甲基转移酶，可通过催化组蛋白H3赖氨酸27的三甲基化（H3K27me3）来改变下游靶基因的表达。研究发现，EZH2在多种肿瘤组织中高表达，与肿瘤的发生、发展、侵袭和转移密切相关；因此，EZH2正成为抗肿瘤治疗中的一个新分子靶点。他泽司他（EPZ-6438）于2020年获批成为首个靶向催化性EZH2的抑制剂，用于治疗上皮样肉瘤。此外，多种EZH2抑制剂正在基础和临床研究中用于肿瘤治疗，并已取得了令人鼓舞的结果。本文系统综述了EZH2抑制剂和基于蛋白酶靶向嵌合体（PROTAC）的EZH2降解剂的研究进展，重点关注其设计策略、构效关系（SARs）以及安全性和临床表现。
