Q1 · MEDICINE
Article
Author: Xu, Dandan ; Li, Yuanqing ; Zhang, Naixia ; Stazi, Giulia ; Chen, Kaixian ; Zhu, Kongkai ; Fan, Shijie ; Zhao, Kehao ; Valente, Sergio ; Luo, Zhongyuan ; Liu, Yanli ; Duan, Wenhu ; Min, Jinrong ; Jiang, Hualiang ; Zhao, Kaiyan ; Kong, Xiangqian ; Ding, Yiluan ; Zhang, Yuanyuan ; Liu, Jingqiu ; Du, Daohai ; Zhu, Licheng ; Zwergel, Clemens ; Luo, Cheng
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.