2. Academic Validation
  3. Discovery of dihydropyridinone derivative as a covalent EZH2 degrader

Discovery of dihydropyridinone derivative as a covalent EZH2 degrader

  • Eur J Med Chem. 2023 Oct 2:261:115825. doi: 10.1016/j.ejmech.2023.115825.
Bin Zhou 1,  Beilei Wang 2,  Fengming Zou 2,  Husheng Mei 1,  Qingwang Liu 2,  Shuang Qi 3,  Wenliang Wang 4,  Rui Jin 5,  Aoli Wang 2,  Yongfei Chen 2,  Feiyang Liu 6,  Wenchao Wang 7,  Jing Liu 8,  Qingsong Liu 9
Affiliations

Affiliations

  • 1 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230026, PR China.
  • 2 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China.
  • 3 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China; Primary Cell Engineering Joint Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China.
  • 4 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Primary Cell Engineering Joint Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China.
  • 5 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China.
  • 6 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China; Primary Cell Engineering Joint Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China.
  • 7 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230026, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China; Primary Cell Engineering Joint Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China.
  • 8 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230026, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China; Primary Cell Engineering Joint Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China. Electronic address: [email protected].
  • 9 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230026, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China; Primary Cell Engineering Joint Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China. Electronic address: [email protected].
PMID: 37826933 DOI: 10.1016/j.ejmech.2023.115825
Abstract

EZH2 is overexpressed in multiple types of Cancer and high expression level of EZH2 correlates with poor prognosis. Besides the regulation of H3K27 trimethylation, EZH2 itself regulates its downstream proteins in a PRC2- and methylation-independent way. Starting from an approved EZH2 Inhibitor EPZ-6438, we used covalent drug design and medicinal chemistry approaches to discover a novel covalent EZH2 Degrader 38, which forms a covalent bond with EZH2 Cys663 and showed strong biochemical activities against EZH2 WT and mutants. Compound 38 exhibited potent antiproliferation effects against both B-cell lymphoma and TNBC cell lines by reducing the levels of H3K27me3 and EZH2. The mass spectrometry, washout and competition experiments confirmed the covalent binding of 38 to EZH2. This study demonstrates that covalent EZH2 degraders could provide an opportunity for the development of promising new drug candidates.

Keywords

Covalent inhibitor; EZH2 degrader; Enhancer of zeste homolog 2; H3K27me3.

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