| 论文编号: |
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| 第一作者所在部门: |
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| 中文论文题目: |
Structure- Based Discovery and Optimization of Furo[3,2-c]pyridin-4(5H)-one Derivatives as Potent and Second Bromodomain (BD2)-Selective Bromo and Extra Terminal Domain (BET) Inhibitors |
| 英文论文题目: |
Structure- Based Discovery and Optimization of Furo[3,2-c]pyridin-4(5H)-one Derivatives as Potent and Second Bromodomain (BD2)-Selective Bromo and Extra Terminal Domain (BET) Inhibitors |
| 作者: |
Junhua Li#, Cheng Zhang#, Hongrui Xu, Chao Wang, Ruibo Dong, Hui Shen, Xiaoxi Zhuang,
Xiaoshan Chen, Qiu Li, Jibu Lu, Maofeng Zhang, Xishan Wu, Kerry M. Loomes, Yulai Zhou, Yan Zhang,
Jinsong Liu, and Yong Xu* |
| 论文出处: |
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| 刊物名称: |
Journal of Medicinal Chemistry |
| 年: |
2022 |
| 卷: |
65 |
| 期: |
7 |
| 页: |
5760-5799 |
| 联系作者: |
Yong Xu |
| 收录类别: |
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| 影响因子: |
8.039 |
| 摘要: |
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-c]pyridin-4(5H)-one derivatives as novel BD2-selective BET inhibitors. The representative compound 8l (XY153) potently bound to BRD4 BD2 with an half-maximum inhibitory concentration (IC50) value of 0.79 nM and displayed 354-fold selectivity over BRD4 BD1. Besides, 8l exhibited 6-fold BRD4 BD2 domain selectivity over other BET BD2 domains. Compound 8l displayed potent antiproliferative activity against multiple tumor cell lines, especially MV4-11 (IC50 = 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. 8l also demonstrated good metabolic stability in vitro. These data indicate that 8l may serve as a new and valuable lead compound for the development of potential therapeutics against acute myeloid leukemia (AML). |
| 英文摘要: |
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