Li Junhua, Zhang Cheng, Xu Hongrui, Wang Chao, Dong Ruibo, Shen Hui, Zhuang Xiaoxi, Chen Xiaoshan, Li Qiu, Lu Jibu, Zhang Maofeng, Wu Xishan, Loomes Kerry M, Zhou Yulai, Zhang Yan, Liu Jinsong, Xu Yong
Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.
J Med Chem. 2022 Apr 14;65(7):5760-5799. doi: 10.1021/acs.jmedchem.2c00100. Epub 2022 Mar 25.
Pan-bromodomain and extra terminal (Pan-BET) inhibitors show profound efficacy but exhibit pharmacology-driven toxicities in clinical trials. The development of domain-selective BET inhibitors to separate efficacy and toxicity is urgently needed. Herein, we report a series of furo[3,2-]pyridin-4(5)-one derivatives as novel BD2-selective BET inhibitors. The representative compound (XY153) potently bound to BRD4 BD2 with an half-maximum inhibitory concentration (IC) value of 0.79 nM and displayed 354-fold selectivity over BRD4 BD1. Besides, exhibited 6-fold BRD4 BD2 domain selectivity over other BET BD2 domains. Compound displayed potent antiproliferative activity against multiple tumor cell lines, especially MV4-11 (IC = 0.55 nM), while showing weak cytotoxicity against the normal lung fibroblast cell line. It highlights the safety profile of this series of BD2 inhibitors. also demonstrated good metabolic stability in vitro. These data indicate that may serve as a new and valuable lead compound for the development of potential therapeutics against acute myeloid leukemia (AML).
泛溴结构域和额外末端（Pan-BET）抑制剂在临床试验中显示出显著疗效，但也表现出由药理学驱动的毒性。迫切需要开发结构域选择性的BET抑制剂以区分疗效和毒性。在此，我们报告了一系列新型的呋[3,2-]吡啶-4(5)-酮衍生物作为BD2选择性BET抑制剂。代表性化合物（XY153）与BRD4 BD2紧密结合，半数最大抑制浓度（IC）值为0.79 nM，对BRD4 BD1的选择性为354倍。此外，与其他BET BD2结构域相比，其对BRD4 BD2结构域的选择性高了6倍。化合物对多种肿瘤细胞系表现出强大的抗增殖活性，尤其是对MV4-11细胞（IC = 0.55 nM），而对正常肺成纤维细胞系的细胞毒性较弱。这突出了该系列BD2抑制剂的安全性。该化合物在体外也表现出良好的代谢稳定性。这些数据表明，该化合物可能成为开发针对急性髓系白血病（AML）潜在治疗药物的一种新的、有价值的先导化合物。
