2. Academic Validation
  3. Covalent inhibitors of EZH2: Design, synthesis and evaluation

Covalent inhibitors of EZH2: Design, synthesis and evaluation

  • Biomed Pharmacother. 2022 Mar;147:112617. doi: 10.1016/j.biopha.2022.112617.
Qiangsheng Zhang 1,  Xinyi Chen 1,  Xi Hu 1,  Xianjie Duan 1,  Guoquan Wan 1,  Lu Li 2,  Qiang Feng 3,  Yiqian Zhang 1,  Ningyu Wang 4,  Luoting Yu 5
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, PR China.
  • 2 Clinical Trial Center, National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
  • 3 College of Chemistry and Life Science, Chengdu Normal University, Chengdu 611130, PR China.
  • 4 School of Life Science and Engineering, Southwest JiaoTong University, Chengdu, Sichuan 611756, PR China. Electronic address: [email protected].
  • 5 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, PR China. Electronic address: [email protected].
PMID: 34998031 DOI: 10.1016/j.biopha.2022.112617
Abstract

The histone lysine methyltransferase EZH2 has been implicated as a key component in Cancer development. Up to date, there are only a few EZH2 covalent inhibitors. In this study, a new series of 3-acrylamido-2-methyl-N-((2-oxo-1,2-dihydropyridin-3-yl) methyl) benzamide derivatives were designed, synthesized, and demonstrated to act as EZH2 covalent inhibitors, among which SKLB-03176 was the most potent compound. SAM competition experiments, mass spectrometry, and washing-out assays proved that SKLB-03176 could covalently bind to the SAM pocket of EZH2. Remarkably, SKLB-03176 exhibited weak activity against other targets, such as 5 histone methyltransferases and more than 30 kinases. Besides, it could inhibit the activity of a variety of EZH2 mutants and significantly inhibit the expression of H3K27Me3 in cells. Furthermore, SKLB-03176 showed no cytotoxicity to normal cells. Our data suggested that SKLB-03176 could be used as a promising lead compound for the development of new EZH2 covalent inhibitors and a valuable chemical tool to study the biological functions of EZH2 or PRC2.

Keywords

Anti-cancer agents; Covalent inhibitor; EZH2; Histone methylation.

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