Structure-Based Discovery and Development of a Series of Potent and Selective Bromodomain and Extra-Terminal Protein Inhibitors

doi:10.1021/acs.jmedchem.9b01094

	Structure-Based Discovery and Development of a Series of Potent and Selective Bromodomain and Extra-Terminal Protein Inhibitors
	Hu, Jianping 3,4; Tian, Chang-Qing 1,3; Damaneh, Mohammadali Soleimani 1,3; Li, Yanlian 4; Cao, Danyan 4; Lv, Kaikai 3,4; Yu, Ting 4; Meng, Tao 4; Chen, Danqi 4; Wang, Xin 4
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2019-09-26
卷号	62 期号:18 页码:8642-8663
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.9b01094
通讯作者	Wang, Ying-Qing(yqwang@simm.ac.cn) ; Miao, Ze-Hong(zhmiao@simm.ac.cn) ; Xiong, Bing(bxiong@simm.ac.cn)
英文摘要	BRD4 has recently emerged as a promising drug target. Therefore, identifying novel inhibitors with distinct properties could enrich their use in anticancer treatment. Guided by the cocrystal structure of hit compound 4 harboring a five-membered-ring linker motif, we quickly identified lead compound 7, which exhibited good antitumor effects in an MM.1S xenograft model by oral administration. Encouraged by its high potency and interesting scaffold, we performed further lead optimization to generate a novel potent series of bromodomain and extra-terminal (BET) inhibitors with a (1,2,4-triazol-5-yl)-3,4-dihydroquinoxalin-2(1H)-one structure. Among them, compound 19 was found to have the best balance of activity, stability, and antitumor efficacy. After confirming its low brain penetration, we conducted comprehensive preclinical studies, including a multiple-species pharmacokinetics profile, extensive cellular mechanism studies, hERG assay, and in vivo antitumor growth effect testing, and we found that compound 19 is a potential BET protein drug candidate for the treatment of cancer.
资助项目	National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002-011-018] ; National Natural Science Foundation of China[81330076]
WOS关键词	BET FAMILY ; BRD4 ; TRANSCRIPTION ; OPTIMIZATION ; EXPRESSION ; CANDIDATE ; CHROMATIN ; READER ; TARGET
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000488334500016
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/282643]
专题	中国科学院上海药物研究所
通讯作者	Wang, Ying-Qing; Miao, Ze-Hong; Xiong, Bing
作者单位	1.Chinese Acad Sci, Shanghai Inst Materia Med, State Key Lab Drug Res, Div Antitumor Pharmacol, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.Icahn Sch Med Mt Sinai, Tisch Canc Inst, Dept Pharmacol Sci, Ctr Chem Biol & Drug Discovery, New York, NY 10029 USA 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Materia Med, State Key Lab Drug Res, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Hu, Jianping,Tian, Chang-Qing,Damaneh, Mohammadali Soleimani,et al. Structure-Based Discovery and Development of a Series of Potent and Selective Bromodomain and Extra-Terminal Protein Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2019,62(18):8642-8663.
APA	Hu, Jianping.,Tian, Chang-Qing.,Damaneh, Mohammadali Soleimani.,Li, Yanlian.,Cao, Danyan.,...&Xiong, Bing.(2019).Structure-Based Discovery and Development of a Series of Potent and Selective Bromodomain and Extra-Terminal Protein Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,62(18),8642-8663.
MLA	Hu, Jianping,et al."Structure-Based Discovery and Development of a Series of Potent and Selective Bromodomain and Extra-Terminal Protein Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY 62.18(2019):8642-8663.