2. Academic Validation
  3. Discovery of Highly Potent and Selective EZH2 Covalent Inhibitors via Incorporating Basic Amines

Discovery of Highly Potent and Selective EZH2 Covalent Inhibitors via Incorporating Basic Amines

  • J Med Chem. 2025 May 22;68(10):10365-10383. doi: 10.1021/acs.jmedchem.5c00545.
Yi Zhang 1,  Qiongyu Shi 2,  Wei Fang 1,  Li Liu 1,  Hong Yang 2,  Xinqiao Liu 1,  Yuting Huang 2 3,  Ying Zhang 2 4,  Xun Huang 2 3 4,  Yuanxiang Wang 1
Affiliations

Affiliations

  • 1 Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
  • 2 Lingang Laboratory, Shanghai 200031, P. R. China.
  • 3 School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 4 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
PMID: 40340349 DOI: 10.1021/acs.jmedchem.5c00545
Abstract

Targeted covalent inhibition is a promising strategy to address the high dose and acquired drug resistance issues of the first-generation EZH2 noncovalent inhibitors. Recently we have reported a new generation of highly potent EZH2 covalent inhibitors, but further optimization to enhance aqueous solubility is required. Here, we described the systematic optimization of EPZ-6438 by preserving the aqueous groups, resulting in the identification of a highly potent and selective EZH2 covalent inhibitor 13, which displayed nanomolar potency in biochemical and cellular assays. Moreover, SAM competition experiments preliminarily confirmed that 13 was noncompetitive with SAM, leading to the remarkable reduction of the H3K27Me3 marker. In addition, 13 exhibited superior cell growth inhibition in the EZH2 mutant Cancer cell lines. The discovery of 13 holds promise for the development of highly potent EZH2 covalent inhibitors.

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