PRC2
EZH2型
化学
体内
组蛋白甲基转移酶
癌症研究
甲基转移酶
共价键
组蛋白
药理学
生物化学
生物
甲基化
遗传学
有机化学
基因
作者
Qiangsheng Zhang,Xinyi Chen,Jiaying Cao,Wan Seok Yang,Guoquan Wan,Qiang Feng,Shuyan Zhou,Hongling Yang,Ningyu Wang,Zhihao Liu,Hongtao Xiao,Yongxia Zhu,Luoting Yu
标识
DOI:10.1021/acs.jmedchem.2c01370
摘要
Enhancer of zeste homologue 2 (EZH2) is the enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2), which plays an important role in post-translational modifications of histones. In this study, we designed and synthesized a new series EZH2 covalent inhibitors that have rarely been reported. Biochemical studies and mass spectrometry provide information that SKLB-03220 could covalently bind to the S-adenosylmethionine (SAM) pocket of EZH2. Besides, SKLB-03220 was highly potent for EZH2MUT, while exhibiting weak activities against other tested histone methyltransferases (HMTs) and kinases. Moreover, SKLB-03220 displayed noteworthy potency against ovarian cancer cell lines and continuously abolished H3K27me3 after washing out. Furthermore, oral administration of SKLB-03220 significantly inhibited tumor growth in PA-1 xenograft model without obvious adverse effects. Taken together, SKLB-03220 is a potent, selective EZH2 covalent inhibitor with noteworthy anticancer efficacy both in vitro and in vivo.
科研通智能强力驱动
Strongly Powered by AbleSci AI