The discovery of SKLB-0335 as a paralog-selective EZH2 covalent inhibitor

Qiangsheng Zhang; Xi Hu; Lu Li; Lidan Zhang; Guoquan Wan; Qiang Feng; Yongxia Zhu; Ningyu Wang; Zhihao Liu; Luoting Yu

doi:10.1039/D0CC04670A

The discovery of SKLB-0335 as a paralog-selective EZH2 covalent inhibitor†

Qiangsheng Zhang,‡^a Xi Hu,‡^a Lu Li,‡^b Lidan Zhang,^a Guoquan Wan,^a Qiang Feng,^c Yongxia Zhu,^d Ningyu Wang,*^e Zhihao Liu*^a and Luoting Yu

*^a

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* Corresponding authors

^a State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P. R. China
E-mail: liuzhihao@scu.edu.cn, yuluot@scu.edu.cn

^b Institute of Clinical Trials, West China Hospital, Sichuan University, Chengdu, Sichuan, P. R. China

^c College of Chemistry and Life Science, Chengdu Normal University, Chengdu 611130, P. R. China

^d Department of Clinical Pharmacy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, P. R. China

^e School of Life Science and Engineering, Southwest JiaoTong University, Chengdu, Sichuan, P. R. China
E-mail: wangny-swjtu@swjtu.edu.cn

Abstract

By targeting the unique Cys663 of EZH2, SKLB-0335 displays high paralog-selectivity on EZH2. Biochemical studies show that SKLB-0335 can covalently bind to EZH2 at its S-adenosylmethionine (SAM) pocket and inhibit H3K27Me3. SKLB-0335 could be an effective chemical probe with which to further investigate the specific biological functions of EZH2.

Chemical Communications

The discovery of SKLB-0335 as a paralog-selective EZH2 covalent inhibitor†

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The discovery of SKLB-0335 as a paralog-selective EZH2 covalent inhibitor

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