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

Daohai Du; Dandan Xu; Licheng Zhu; Giulia Stazi; Clemens Zwergel; Yanli Liu; Zhongyuan Luo; Yuanqing Li; Yuanyuan Zhang; Kongkai Zhu; Yiluan Ding; Jingqiu Liu; Shijie Fan; Kaiyan Zhao; Naixia Zhang; Xiangqian Kong; Hualiang Jiang; Kaixian Chen; Kehao Zhao; Sergio Valente; Jinrong Min; Wenhu Duan; Cheng Luo

doi:10.1021/acs.jmedchem.0c02261

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. Epub 2021 Jun 2.

Authors

Daohai Du^{1

2}, Dandan Xu^{3

4}, Licheng Zhu^{5

6

7}, Giulia Stazi⁸, Clemens Zwergel⁸, Yanli Liu^{5

6

9}, Zhongyuan Luo^{1

2}, Yuanqing Li^{2

4}, Yuanyuan Zhang², Kongkai Zhu¹⁰, Yiluan Ding¹¹, Jingqiu Liu², Shijie Fan², Kaiyan Zhao^{3

4}, Naixia Zhang¹¹, Xiangqian Kong¹², Hualiang Jiang², Kaixian Chen², Kehao Zhao¹³, Sergio Valente⁸, 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.

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 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Astemizole / analogs & derivatives*
Astemizole / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Repositioning
Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors*
Enhancer of Zeste Homolog 2 Protein / metabolism
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology*
Humans
Molecular Docking Simulation
Molecular Structure
Polycomb Repressive Complex 2 / antagonists & inhibitors*
Polycomb Repressive Complex 2 / metabolism
Protein Binding / drug effects*
Structure-Activity Relationship

Substances

EED protein, human
Enzyme Inhibitors
Astemizole
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Polycomb Repressive Complex 2

Grants and funding

106169/ZZ14/Z/WT_/Wellcome Trust/United Kingdom