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Identification of catalytic and non-catalytic activity inhibitors against PRC2-EZH2 complex through multiple high-throughput screening campaigns

文献类型：期刊论文

作者Zhou, Yan2,3; Du, Dao-Hai4; Wang, Jia2,3; Cai, Xiao-Qing2,3; Deng, Alicia X.2,3; Nosjean, Olivier1; Boutin, Jean A.1; Renard, Pierre1; Yang, De-Hua2,3; Luo, Cheng4
刊名CHEMICAL BIOLOGY & DRUG DESIGN
出版日期2020-05-25
页码27
关键词embryonic ectoderm development Enhancer of zeste homolog 2 fluorescence polarization high-throughput screening homogenous time-resolved fluorescence inhibitor polycomb repressive complex 2
ISSN号1747-0277
DOI10.1111/cbdd.13702
通讯作者Yang, De-Hua(dhyang@simm.ac.cn) ; Luo, Cheng(cluo@simm.ac.cn) ; Wang, Ming-Wei(mwwang@simm.ac.cn)
英文摘要Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) along with embryonic ectoderm development (EED) and suppressor of zeste 12 (SUZ12), which implements transcriptional repression mainly by depositing trimethylation marks at lysine 27 of histone H3 (H3K27me3). Its catalytic activity is closely correlated with the stability of PRC2, and somatic activating mutation of EZH2 Y641F within the catalytic SET domain drives tumor aggressiveness, drug resistance, and poor prognosis. Here, we report two high-throughput screening (HTS) campaigns targeting EZH2 Y641F and EZH2-EED interaction, respectively. For the EZH2 Y641F mutant, the HTS campaign involved a library of 250,000 compounds using a homogenous time-resolved fluorescence (HTRF) assay and identified 162 hits, while 60,160 compounds were screened against EZH2-EED interaction with a fluorescence polarization (FP) assay resulting in 97 hits. Among the 162 EZH2 Y641F inhibitors, 38 also suppressed EZH2-EED interaction and 80 showed inhibitory effects on the wide-type (WT) EZH2. Meanwhile, 10 of the 97 EZH2-EED interaction inhibitors were active against WT EZH2. These hit compounds provide useful tools for the development of novel PRC2-EZH2 inhibitors targeting its catalytic and non-catalytic activities.
WOS关键词FLUORESCENCE POLARIZATION ASSAY ; HISTONE METHYLTRANSFERASE EZH2 ; LYSINE 27 ; SELECTIVE INHIBITOR ; CANCER-CELLS ; LYMPHOMA ; H3K27 ; PRC2 ; H3 ; HYPERTRIMETHYLATION
资助项目National Science and Technology Major Project[2018ZX09711002] ; K. C. Wong Education Foundation
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000535070200001
出版者WILEY
源URL[http://119.78.100.183/handle/2S10ELR8/280041]  
专题新药研究国家重点实验室
通讯作者Yang, De-Hua; Luo, Cheng; Wang, Ming-Wei
作者单位1.Labs Servier, Neuilly Sur Seine, France
2.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Fudan Univ, Sch Basic Med Sci, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Zhou, Yan,Du, Dao-Hai,Wang, Jia,et al. Identification of catalytic and non-catalytic activity inhibitors against PRC2-EZH2 complex through multiple high-throughput screening campaigns[J]. CHEMICAL BIOLOGY & DRUG DESIGN,2020:27.
APA Zhou, Yan.,Du, Dao-Hai.,Wang, Jia.,Cai, Xiao-Qing.,Deng, Alicia X..,...&Wang, Ming-Wei.(2020).Identification of catalytic and non-catalytic activity inhibitors against PRC2-EZH2 complex through multiple high-throughput screening campaigns.CHEMICAL BIOLOGY & DRUG DESIGN,27.
MLA Zhou, Yan,et al."Identification of catalytic and non-catalytic activity inhibitors against PRC2-EZH2 complex through multiple high-throughput screening campaigns".CHEMICAL BIOLOGY & DRUG DESIGN (2020):27.

入库方式： OAI收割

来源：上海药物研究所

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