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	Nmr-based platform for fragment-based lead discovery used in screening brd4-targeted compounds
	Yu, Jun-lan1,2; Chen, Tian-tian3; Zhou, Chen1,2; Lian, Fu-lin1,2; Tang, Xu-long1,2; Wen, Yi1,2; Shen, Jing-kang4; Xu, Ye-chun3; Xiong, Bing4; Zhang, Nai-xia1,2
刊名	Acta pharmacologica sinica
	2016-07-01
卷号	37期号:7页码:984-993
关键词	Fragment-based lead discovery Nmr Bromodomain Brd4 inhibitors
ISSN号	1671-4083
DOI	10.1038/aps.2016.19
通讯作者	Xiong, bing(bxiong@simm.ac.cn) ; Zhang, nai-xia(nxzhang@mail.shcnc.ac.cn)
英文摘要	Aim: fragment-based lead discovery (fbld) is a complementary approach in drug research and development. in this study, we established an nmr-based fbld platform that was used to screen novel scaffolds targeting human bromodomain of brd4, and investigated the binding interactions between hit compounds and the target protein. methods: 1d nmr techniques were primarily used to generate the fragment library and to screen compounds. the inhibitory activity of hits on the first bromodomain of brd4 [brd4(i)] was examined using fluorescence anisotropy binding assay. 2d nmr and x-ray crystallography were applied to characterize the binding interactions between hit compounds and the target protein. results: an nmr-based fragment library containing 539 compounds was established, which were clustered into 56 groups (8-10 compounds in each group). eight hits with new scaffolds were found to inhibit brd4(i). four out of the 8 hits (compounds 1, 2, 8 and 9) had ic50 values of 100-260 mu mol/l, demonstrating their potential for further brd4-targeted hit-to-lead optimization. analysis of the binding interactions revealed that compounds 1 and 2 shared a common quinazolin core structure and bound to brd4(i) in a non-acetylated lysine mimetic mode. conclusion: an nmr-based platform for fbld was established and used in discovery of brd4-targeted compounds. four potential hit-to-lead optimization candidates have been found, two of them bound to brd4(i) in a non-acetylated lysine mimetic mode, being selective brd4(i) inhibitors.
WOS关键词	BET BROMODOMAIN INHIBITORS ; CHEMICAL-SHIFT INDEX ; DRUG DISCOVERY ; DNA METHYLATION ; SELECTIVE-INHIBITION ; TERMINAL DOMAIN ; EPIGENETICS ; BINDING ; CANCER ; POTENT
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
WOS类目	Chemistry, Multidisciplinary ; Pharmacology & Pharmacy
语种	英语
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000379430900013
内容类型	期刊论文
URI标识	http://www.corc.org.cn/handle/1471x/2374588
专题	中国科学院大学
通讯作者	Xiong, Bing; Zhang, Nai-xia
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Yu, Jun-lan,Chen, Tian-tian,Zhou, Chen,et al. Nmr-based platform for fragment-based lead discovery used in screening brd4-targeted compounds[J]. Acta pharmacologica sinica,2016,37(7):984-993.
APA	Yu, Jun-lan.,Chen, Tian-tian.,Zhou, Chen.,Lian, Fu-lin.,Tang, Xu-long.,...&Zhang, Nai-xia.(2016).Nmr-based platform for fragment-based lead discovery used in screening brd4-targeted compounds.Acta pharmacologica sinica,37(7),984-993.
MLA	Yu, Jun-lan,et al."Nmr-based platform for fragment-based lead discovery used in screening brd4-targeted compounds".Acta pharmacologica sinica 37.7(2016):984-993.

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