2. Academic Validation
  3. Discovery of a Novel Covalent EZH2 Inhibitor Based on Tazemetostat Scaffold for the Treatment of Ovarian Cancer

Discovery of a Novel Covalent EZH2 Inhibitor Based on Tazemetostat Scaffold for the Treatment of Ovarian Cancer

  • J Med Chem. 2023 Feb 9;66(3):1725-1741. doi: 10.1021/acs.jmedchem.2c01370.
Qiangsheng Zhang 1,  Xinyi Chen 1,  Jiaying Cao 1,  Wan Yang 1,  Guoquan Wan 1,  Qiang Feng 2,  Shuyan Zhou 1,  Hongling Yang 1,  Ningyu Wang 3,  Zhihao Liu 1 4,  Hongtao Xiao 5,  Yongxia Zhu 5,  Luoting Yu 1
Affiliations

Affiliations

  • 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.
  • 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.
  • 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.
PMID: 36692394 DOI: 10.1021/acs.jmedchem.2c01370
Abstract

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.

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