Discovery of a series of dihydroquinoxalin-2(1H)-ones as selective BET inhibitors from a dual PLK1-BRD4 inhibitor

doi:10.1016/j.ejmech.2017.05.049

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	Discovery of a series of dihydroquinoxalin-2(1H)-ones as selective BET inhibitors from a dual PLK1-BRD4 inhibitor
	Hu, Jianping 1,2; Wang, Yingqing3 ; Li, Yanlian 1; Xu, Lin 2,3; Cao, Danyan 1; Song, ShanShan 3; Damaneh, Mohammadali Soleimani 2,3; Wang, Xin1 ; Meng, Tao1 ; Chen, Yue-Lei1
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2017-09-08
卷号	137 页码:176-195
关键词	BRD4 inhibitor Kinase BI-2536 Dihydroquinoxalin-2(1H)-one
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2017.05.049
文献子类	Article
英文摘要	Recent years have seen much effort to discover new chemotypes of BRD4 inhibitors. Interestingly, some kinase inhibitors have been demonstrated to be potent bromodomain inhibitors, especially the PLK1 inhibitor BI-2536 and the JAK2 inhibitor TG101209, which can bind to BRD4 with IC50 values of 0.025 mu M and 0.13 mu M, respectively. Although the concept of dual inhibition is intriguing, selective BRD4 inhibitors are preferred as they may diminish off-target effects and provide more flexibility in anticancer drug combination therapy. Inspired by BI-2536, we designed and prepared a series of dihydroquinoxalin2(1H)-one derivatives as selective bromodomain inhibitors. We found compound 54 had slightly higher activity than (+)-JQ1 in the fluorescence anisotropy assay and potent antiproliferative cellular activity in the MM.1S cell line. We have successfully solved the cocrystal structure of 52 in complex with BRD4-BD1, providing a solid structural basis for the binding mode of compounds of this series. Compound 54 exhibited high selectivity over most non-BET subfamily members and did not show bioactivity towards the PLK1 kinase at 10 or 1 mu M. From in vivo studies, compound 54 demonstrated a good PK profile, and the results from in vivo pharmacological studies clearly showed the efficacy of 54 in the mouse MM.1S xenograft model. (C) 2017 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[81330076] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program" of China[2014ZX09507-002] ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020318]
WOS关键词	SMALL-MOLECULE INHIBITORS ; BROMODOMAIN LIGANDS ; DRUG DISCOVERY ; C-MYC ; BRD4 ; READER ; KINASE ; ACETYLATION ; BINDING ; TARGET
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000407412200015
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272486]
专题	药理学第一研究室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药物化学研究室
通讯作者	Shen, Jingkang; Miao, Zehong; Xiong, Bing
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Hu, Jianping,Wang, Yingqing,Li, Yanlian,et al. Discovery of a series of dihydroquinoxalin-2(1H)-ones as selective BET inhibitors from a dual PLK1-BRD4 inhibitor[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2017,137:176-195.
APA	Hu, Jianping.,Wang, Yingqing.,Li, Yanlian.,Xu, Lin.,Cao, Danyan.,...&Xiong, Bing.(2017).Discovery of a series of dihydroquinoxalin-2(1H)-ones as selective BET inhibitors from a dual PLK1-BRD4 inhibitor.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,137,176-195.
MLA	Hu, Jianping,et al."Discovery of a series of dihydroquinoxalin-2(1H)-ones as selective BET inhibitors from a dual PLK1-BRD4 inhibitor".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 137(2017):176-195.