机构：[1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, 17#3rd Section, Ren Min South Road, Chengdu 610041, P. R. China.四川大学华西医院[2]College of Chemistry and Life Science, Chengdu Normal University, Chengdu 611130, P. R. China.[3]School of Life Science and Engineering, Southwest JiaoTong University, Chengdu 611756, Sichuan, P. R. China.[4]Laboratory of Emergency Medicine, Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.四川大学华西医院[5]Department of Clinical Pharmacy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, P. R. China.临床药学部临床药学部四川省人民医院四川省肿瘤医院
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.
第一作者机构：[1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, 17#3rd Section, Ren Min South Road, Chengdu 610041, P. R. China.
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推荐引用方式(GB/T 7714)：
Zhang Qiangsheng,Chen Xinyi,Cao Jiaying,et al.Discovery of a Novel Covalent EZH2 Inhibitor Based on Tazemetostat Scaffold for the Treatment of Ovarian Cancer[J].JOURNAL OF MEDICINAL CHEMISTRY.2023,66(3):1725-1741.doi:10.1021/acs.jmedchem.2c01370.
APA：
Zhang Qiangsheng,Chen Xinyi,Cao Jiaying,Yang Wan,Wan Guoquan...&Yu Luoting.(2023).Discovery of a Novel Covalent EZH2 Inhibitor Based on Tazemetostat Scaffold for the Treatment of Ovarian Cancer.JOURNAL OF MEDICINAL CHEMISTRY,66,(3)
MLA：
Zhang Qiangsheng,et al."Discovery of a Novel Covalent EZH2 Inhibitor Based on Tazemetostat Scaffold for the Treatment of Ovarian Cancer".JOURNAL OF MEDICINAL CHEMISTRY 66..3(2023):1725-1741
医学