Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays

doi:10.1016/j.bmcl.2017.03.012

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

	Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays
	Sun, Zhongya 2; Zhang, Hao 3,4; Chen, Zhifeng 1; Xie, Yiqian 3; Jiang, Hao 3; Chen, Limin 2; Ding, Hong3 ; Zhang, Yuanyuan 3; Jiang, Hualiang3 ; Zheng, Mingyue3
刊名	BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
	2017-05-01
卷号	27 期号:9 页码:2003-2009
关键词	BRD4 inhibitor High-throughput screening Crystallography
ISSN号	0960-894X
DOI	10.1016/j.bmcl.2017.03.012
文献子类	Article
英文摘要	As an epigenetic reader, BRD4 regulates the transcription of important downstream genes that are essential for the survival of tumor cells. Small molecular inhibitors targeting the first bromodomain of BRD4 (BRD4-BD1) have showed promising potentials in the therapies of BRD4-related cancers. Through AlphaScreen-based high-throughput screening assay, a novel small molecular inhibitor was identified, and named DCBD-005, which inhibited the binding between BRD4-BD1 and acetylated lysines with an IC50 value of 0.81 +/- 0.03 mu M. The compound DCBD-005 effectively inhibited the viability, caused cell cycle arrest, and induced apoptosis in human leukemia MV4-11 cells. Moreover, the crystal structure of compound DCBD-005 with the BRD4-BD1 was determined at 1.72 angstrom resolution, which revealed the binding mechanism of the leading compound, and also provided solid basis for further structure-based optimization. These results indicated that this novel BRD4-BD1 inhibitor DCBD-005 is promising to be developed into a drug candidate in the treatment of BRD4-related diseases. (C) 2017 Published by Elsevier Ltd.
资助项目	Computer Network Information Center, Chinese Academy of Sciences[00000000] ; Guangdong Supercomputing Center[2015-446] ; Ministry of Science and Technology of China[2015CB910304] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[91229205] ; 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[81430084] ; Fund of State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science[TMC201505]
WOS关键词	BET BROMODOMAIN INHIBITION ; GENE-EXPRESSION ; CHROMATIN ; TARGET ; CANCER ; POTENT ; OPTIMIZATION ; ACETYLATION ; RECOGNITION ; ACTIVATION
WOS研究方向	Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000399862800025
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272688]
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	Chen, Limin; Ding, Hong; Luo, Cheng
作者单位	1.ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China 2.Nanchang Univ, Sch Pharm, 461 Bayi Rd, Nanchang 330006, Jiangxi, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 4.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China;
推荐引用方式 GB/T 7714	Sun, Zhongya,Zhang, Hao,Chen, Zhifeng,et al. Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2017,27(9):2003-2009.
APA	Sun, Zhongya.,Zhang, Hao.,Chen, Zhifeng.,Xie, Yiqian.,Jiang, Hao.,...&Luo, Cheng.(2017).Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,27(9),2003-2009.
MLA	Sun, Zhongya,et al."Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 27.9(2017):2003-2009.