Gavai Ashvinikumar V, Norris Derek, Delucca George, Tortolani David, Tokarski John S, Dodd Dharmpal, O'Malley Daniel, Zhao Yufen, Quesnelle Claude, Gill Patrice, Vaccaro Wayne, Huynh Tram, Ahuja Vijay, Han Wen-Ching, Mussari Christopher, Harikrishnan Lalgudi, Kamau Muthoni, Poss Michael, Sheriff Steven, Yan Chunhong, Marsilio Frank, Menard Krista, Wen Mei-Li, Rampulla Richard, Wu Dauh-Rurng, Li Jianqing, Zhang Huiping, Li Peng, Sun Dawn, Yip Henry, Traeger Sarah C, Zhang Yingru, Mathur Arvind, Zhang Haiying, Huang Christine, Yang Zheng, Ranasinghe Asoka, Everlof Gerry, Raghavan Nirmala, Tye Ching Kim, Wee Susan, Hunt John T, Vite Gregory, Westhouse Richard, Lee Francis Y
Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
J Med Chem. 2021 Oct 14;64(19):14247-14265. doi: 10.1021/acs.jmedchem.1c00625. Epub 2021 Sep 20.
Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit , a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.
抑制衔接蛋白的溴结构域和额外末端（BET）家族是一种针对关键癌基因（如c-MYC）转录调控的有吸引力的策略。从筛选命中物开始，通过构效关系和蛋白质结构导向的药物设计相结合，发现了一种取向不同的咔唑，它与BET家族中保守的色氨酸、脯氨酸和苯丙氨酸（WPF）架具有良好的结合。识别出一个额外的亲脂性口袋并进行官能团优化以优化药代动力学（PK）性质，最终发现了在结合和功能测定中具有优异效力的（BMS-986158）。基于其良好的PK谱和在一系列血液学和实体瘤模型中的强大体内活性，BMS-986158被选为临床评估的候选药物。
