Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction PMID: 34077206

ADC Targets in Oncology

2026-04-10

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

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.

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 K_d 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.