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.

Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2–EED Interaction / Du, Daohai; Xu, Dandan; Zhu, Licheng; Stazi, Giulia; Zwergel, Clemens; Liu, Yanli; Luo, Zhongyuan; Li, Yuanqing; Zhang, Yuanyuan; Zhu, Kongkai; Ding, Yiluan; Liu, Jingqiu; Fan, Shijie; Zhao, Kaiyan; Zhang, Naixia; Kong, Xiangqian; Jiang, Hualiang; Chen, Kaixian; Zhao, Kehao; Valente, Sergio; Min, Jinrong; Duan, Wenhu; Luo, Cheng. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 64:12(2021), pp. 8194-8207. [10.1021/acs.jmedchem.0c02261]

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

Zwergel, Clemens;Valente, Sergio
;
2021

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.
2021
EZH2; EED; astemizole; PRC2; interaction inhibitor
01 Pubblicazione su rivista::01a Articolo in rivista
Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2–EED Interaction / Du, Daohai; Xu, Dandan; Zhu, Licheng; Stazi, Giulia; Zwergel, Clemens; Liu, Yanli; Luo, Zhongyuan; Li, Yuanqing; Zhang, Yuanyuan; Zhu, Kongkai; Ding, Yiluan; Liu, Jingqiu; Fan, Shijie; Zhao, Kaiyan; Zhang, Naixia; Kong, Xiangqian; Jiang, Hualiang; Chen, Kaixian; Zhao, Kehao; Valente, Sergio; Min, Jinrong; Duan, Wenhu; Luo, Cheng. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 64:12(2021), pp. 8194-8207. [10.1021/acs.jmedchem.0c02261]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1550470
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