Development of a high-throughput fluorescence polarization assay for the discovery of EZH2-EED interaction inhibitors

doi:10.1038/aps.2017.59

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	Development of a high-throughput fluorescence polarization assay for the discovery of EZH2-EED interaction inhibitors
	Zhu, Mao-rong 3,4; Du, Dao-hai 3; Hu, Jun-chi 3; Li, Lian-chun 3; Liu, Jing-qiu 3; Ding, Hong3 ; Kong, Xiang-qian 1,3; Jiang, Hua-liang3 ; Chen, Kai-xian3 ; Luo, Cheng2,3
刊名	ACTA PHARMACOLOGICA SINICA
	2018-02
卷号	39 期号:2 页码:302-310
关键词	PRC2 EZH2 EED protein-protein interaction fluorescence polarization high-throughput screening apomorphine hydrochloride oxyphenbutazone nifedipine ergonovine maleate
ISSN号	1671-4083
DOI	10.1038/aps.2017.59
文献子类	Article
英文摘要	Aberrant activity of enhancer of zeste homolog 2 (EZH2) is associated with a wide range of human cancers. The interaction of EZH2 with embryonic ectoderm development (EED) is required for EZH2's catalytic activity. Inhibition of the EZH2-EED complex thus represents a novel strategy for interfering with the oncogenic potentials of EZH2 by targeting both its catalytic and non-catalytic functions. To date, there have been no reported high-throughput screening (HTS) assays for inhibitors acting at the EZH2-EED interface. In this study, we developed a fluorescence polarization (FP)-based HTS system for the discovery of EZH2-EED interaction inhibitors. The tracer peptide sequences, positions of fluorescein labeling, and a variety of physicochemical conditions were optimized. The high Z' factors (>0.9) at a variety of DMSO concentrations suggested that this system is robust and suitable for HTS. The minimal sequence requirement for the EZH2-EED interaction was determined by using this system. A pilot screening of an in-house compound library containing 1600 FDA-approved drugs identified four compounds (apomorphine hydrochloride, oxyphenbutazone, nifedipine and ergonovine maleate) as potential EZH2-EED interaction inhibitors.
资助项目	Ministry of Science and Technology of China[2015CB910304] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[21210003] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[91313000] ; State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science[TMC201505]
WOS关键词	PROTEIN-PROTEIN INTERACTIONS ; SMALL-MOLECULE INHIBITORS ; REPRESSIVE COMPLEX 2 ; B-CELL LYMPHOMAS ; HISTONE H3 ; METHYLTRANSFERASE ACTIVITY ; PROSTATE-CANCER ; DRUG DISCOVERY ; POLYCOMB ; EXPRESSION
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:6163696
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000423868000016
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279938]
专题	药物发现与设计中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Luo, Cheng
作者单位	1.Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD 21287 USA 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.Univ Sci & Technol China, Nano Sci & Technol Inst, Suzhou 215123, Peoples R China;
推荐引用方式 GB/T 7714	Zhu, Mao-rong,Du, Dao-hai,Hu, Jun-chi,et al. Development of a high-throughput fluorescence polarization assay for the discovery of EZH2-EED interaction inhibitors[J]. ACTA PHARMACOLOGICA SINICA,2018,39(2):302-310.
APA	Zhu, Mao-rong.,Du, Dao-hai.,Hu, Jun-chi.,Li, Lian-chun.,Liu, Jing-qiu.,...&Luo, Cheng.(2018).Development of a high-throughput fluorescence polarization assay for the discovery of EZH2-EED interaction inhibitors.ACTA PHARMACOLOGICA SINICA,39(2),302-310.
MLA	Zhu, Mao-rong,et al."Development of a high-throughput fluorescence polarization assay for the discovery of EZH2-EED interaction inhibitors".ACTA PHARMACOLOGICA SINICA 39.2(2018):302-310.