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

文献类型：期刊论文

作者Hu, Jianping3,4; Tian, Chang-Qing1,3; Damaneh, Mohammadali Soleimani1,3; Li, Yanlian4; Cao, Danyan4; Lv, Kaikai3,4; Yu, Ting4; Meng, Tao4; Chen, Danqi4; Wang, Xin4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2019-09-26
卷号62期号:18页码:8642-8663
ISSN号0022-2623
DOI10.1021/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.
WOS关键词BET FAMILY ; BRD4 ; TRANSCRIPTION ; OPTIMIZATION ; EXPRESSION ; CANDIDATE ; CHROMATIN ; READER ; TARGET
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研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000488334500016
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/282643]  
专题新药研究国家重点实验室
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.

入库方式： OAI收割

来源：上海药物研究所

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