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

doi:10.1021/acs.jmedchem.0c02261

	Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction
	Du, Daohai 2,3; Xu, Dandan 4,5; Zhu, Licheng 6,7,8,9; Stazi, Giulia 10; Zwergel, Clemens 10; Liu, Yanli 6,7,8,11; Luo, Zhongyuan 2,3; Li, Yuanqing 3,5; Zhang, Yuanyuan 3; Zhu, Kongkai 12
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2021-06-24
卷号	64 期号:12 页码:8194-8207
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.0c02261
通讯作者	Valente, Sergio(sergio.valente@uniroma1.it) ; Min, Jinrong(jr.min@utoronto.ca) ; Duan, Wenhu(whduan@simm.ac.cn) ; Luo, Cheng(cluo@simm.ac.cn)
英文摘要	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 angstrom. 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 mu M. 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.
WOS关键词	REPRESSIVE COMPLEX 2 ; METHYLTRANSFERASE ACTIVITY ; SELECTIVE-INHIBITION ; SOMATIC MUTATIONS ; ACCURATE DOCKING ; PROTEIN EED ; POLYCOMB ; ENHANCER ; CANCER ; POTENT
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000668340800017
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/296900]
专题	中国科学院上海药物研究所
通讯作者	Valente, Sergio; Min, Jinrong; Duan, Wenhu; Luo, Cheng
作者单位	1.Yantai Univ, Collaborat Innovat Ctr Adv Drug Delivery Syst & B, Yantai 264005, Peoples R China 2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Jiangsu, Peoples R China 3.Chinese Acad Sci, Drug Discovery & Design Ctr, Ctr Chem Biol, State Key Lab Drug Res,Shanghai Inst Mat Med, Shanghai 210203, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 6.Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada 7.Univ Toronto, Dept Physiol, Toronto, ON M5G 1L7, Canada 8.Cent China Normal Univ, Sch Life Sci, Hubei Key Lab Genet Regulat & Integrat Biol, Wuhan 430079, Peoples R China 9.Jinggangshan Univ, Sch Life Sci, Jian 343009, Jiangxi, Peoples R China 10.Sapienza Univ Rome, Dept Drug Chem & Technol, I-00185 Rome, Italy
推荐引用方式 GB/T 7714	Du, Daohai,Xu, Dandan,Zhu, Licheng,et al. Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(12):8194-8207.
APA	Du, Daohai.,Xu, Dandan.,Zhu, Licheng.,Stazi, Giulia.,Zwergel, Clemens.,...&Luo, Cheng.(2021).Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction.JOURNAL OF MEDICINAL CHEMISTRY,64(12),8194-8207.
MLA	Du, Daohai,et al."Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction".JOURNAL OF MEDICINAL CHEMISTRY 64.12(2021):8194-8207.