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

Jianping Hu, Chang Qing Tian, Mohammadali Soleimani Damaneh, Yanlian Li, Danyan Cao, Kaikai Lv, Ting Yu, Tao Meng, Danqi Chen, Xin Wang, Lin Chen, Jian Li, Shan Shan Song, Xia Juan Huan, Lihuai Qin, Jingkang Shen, Ying Qing Wang, Ze Hong Miao, Bing Xiong

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)8642-8663
Number of pages22
JournalJournal of Medicinal Chemistry
Volume62
Issue number18
DOIs
StatePublished - 26 Sep 2019

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