Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2–EED Interaction
| Autor: | Licheng Zhu, Wenhu Duan, Jinrong Min, Kongkai Zhu, Shijie Fan, Giulia Stazi, Clemens Zwergel, Xiangqian Kong, Hualiang Jiang, Kaiyan Zhao, Daohai Du, Yuanqing Li, Naixia Zhang, Yuanyuan Zhang, Yanli Liu, Kehao Zhao, Sergio Valente, Zhongyuan Luo, Yiluan Ding, Dandan Xu, Jingqiu Liu, Cheng Luo, Kaixian Chen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
EZH2
EED astemizole PRC2 interaction inhibitor Chemical probe macromolecular substances 01 natural sciences 03 medical and health sciences Structure-Activity Relationship Cell Line Tumor Drug Discovery medicine Humans Enhancer of Zeste Homolog 2 Protein Enzyme Inhibitors 030304 developmental biology Cell Proliferation 0303 health sciences biology Molecular Structure Chemistry Drug Repositioning Polycomb Repressive Complex 2 Core protein Cell cycle Astemizole Small molecule 0104 chemical sciences Cell biology Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Cancer cell biology.protein Molecular Medicine medicine.drug Protein Binding |
| Popis: | 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 A. 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. |
| Databáze: | OpenAIRE |
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