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

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posted on 2019-09-16, 15:12 authored by 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
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.

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