2. Academic Validation
  3. Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction

Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction

  • J Med Chem. 2021 Jun 24;64(12):8194-8207. doi: 10.1021/acs.jmedchem.0c02261.
Daohai Du 1 2,  Dandan Xu 3 4,  Licheng Zhu 5 6 7,  Giulia Stazi 8,  Clemens Zwergel 8,  Yanli Liu 5 6 9,  Zhongyuan Luo 1 2,  Yuanqing Li 2 4,  Yuanyuan Zhang 2,  Kongkai Zhu 10,  Yiluan Ding 11,  Jingqiu Liu 2,  Shijie Fan 2,  Kaiyan Zhao 3 4,  Naixia Zhang 11,  Xiangqian Kong 12,  Hualiang Jiang 2,  Kaixian Chen 2,  Kehao Zhao 13,  Sergio Valente 8,  Jinrong Min 5 6,  Wenhu Duan 3 4,  Cheng Luo 1 2 4 13 14
Affiliations

Affiliations

  • 1 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023 Jiangsu, China.
  • 2 Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 210203, China.
  • 3 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 Structural Genomics Consortium and Department of Physiology, University of Toronto, Toronto M5G1L7 Ontario, Canada.
  • 6 Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, China.
  • 7 School of Life Sciences, Jinggangshan University, Ji'an 343009 Jiangxi, China.
  • 8 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome 00185, Italy.
  • 9 College of Pharmaceutical Sciences, Soochow University, Suzhou 215123 Jiangsu, China.
  • 10 School of Biological Science and Technology, University of Jinan; Jinan 250022, China.
  • 11 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 12 Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 13 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education; Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
  • 14 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
PMID: 34077206 DOI: 10.1021/acs.jmedchem.0c02261
Abstract

Disruption of EZH2-embryonic ectoderm development (EED) protein-protein interaction (PPI) is a new promising Cancer therapeutic strategy. We have previously reported the discovery of astemizole, a small-molecule inhibitor targeting the EZH2-EED PPI. Herein, we report the cocrystal structure of EED in complex with astemizole at 2.15 Å. The structure elucidates the detailed binding mode of astemizole to EED and provides a structure-guided design for the discovery of a novel EZH2-EED interaction inhibitor, DC-PRC2in-01, with an affinity Kd of 4.56 μM. DC-PRC2in-01 destabilizes the PRC2 complex, thereby leading to the degradation of PRC2 core proteins and the decrease of global H3K27me3 levels in Cancer cells. The proliferation of PRC2-driven lymphomas cells is effectively inhibited, and the cell cycle is arrested in the G0/G1 phase. Together, these data demonstrate that DC-PRC2in-01 could be an effective chemical probe for investigating the PRC2-related physiology and pathology and providing a promising chemical scaffold for further development.

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