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

作者：Jianping Hu, Changqing Tian, Mohammadali Soleimani Damaneh, Yanlian Li, Danyan Cao, Kaikai Lv, Ting Yu, Tao Meng, Danqi Chen, Xin Wang, Lin Chen, Jian Li, Shanshan Song, Xia‐Juan Huan, Lihuai Qin, Jingkang Shen, Ying-Qing Wang, Ze‐Hong Miao, Bing Xiong · 发表于：Journal of Medicinal Chemistry · 年份：2019 · DOI：10.1021/acs.jmedchem.9b01094 · 被引用次数：38 · 研究领域：Protein Degradation and Inhibitors、Multiple Myeloma Research and Treatments、Ubiquitin and proteasome pathways

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(1 H )-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.