Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2–EED Interaction,Journal of Medicinal Chemistry

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Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2–EED Interaction
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-06-02 , 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}

Affiliation

School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023 Jiangsu, China.
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.
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Structural Genomics Consortium and Department of Physiology, University of Toronto, Toronto M5G1L7 Ontario, Canada.
Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, China.
School of Life Sciences, Jinggangshan University, Ji'an 343009 Jiangxi, China.
Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome 00185, Italy.
College of Pharmaceutical Sciences, Soochow University, Suzhou 215123 Jiangsu, China.
School of Biological Science and Technology, University of Jinan; Jinan 250022, China.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
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.
School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.

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.

中文翻译：

靶向EZH2-EED相互作用的小分子PRC2抑制剂的结构引导开发

EZH2-胚胎外胚层发育（EED）蛋白质-蛋白质相互作用（PPI）的破坏是一种新的有前途的癌症治疗策略。我们之前曾报道过阿司咪唑的发现，这是一种靶向 EZH2-EED PPI 的小分子抑制剂。在此，我们报告了 EED 与阿司咪唑复合物在 2.15 Å 处的共晶结构。该结构阐明了阿司咪唑与 EED 的详细结合模式，并为发现具有亲和力K _d的新型 EZH2-EED 相互作用抑制剂 DC-PRC2in-01 提供了结构指导设计4.56 μM。DC-PRC2in-01 使PRC2 复合物不稳定，从而导致PRC2 核心蛋白的降解和癌细胞中整体H3K27me3 水平的降低。有效抑制PRC2驱动的淋巴瘤细胞增殖，细胞周期停滞在G0/G1期。总之，这些数据表明 DC-PRC2in-01 可能是一种有效的化学探针，用于研究与 PRC2 相关的生理学和病理学，并为进一步开发提供有前景的化学支架。

更新日期：2021-06-24

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