Discovery of the First BRD4 Second Bromodomain (BD2)-Selective Inhibitors
文献类型：期刊论文
| 作者 | Li, Junhua3; Hu, Qingqing3; Zhu, Run1,3; Dong, Ruibo3,5; Shen, Hui3; Hu, Jiankang3; Zhang, Cheng3; Zhang, Xiaohan4; Xu, Tingting3; Xiang, Qiuping2 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2024-11-27 |
| 卷号 | 67期号:23页码:21577-21616 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.4c02516 |
| 通讯作者 | Zhao, Linxiang(linxiang.zhao@vip.sina.com) ; Wu, Xishan(wu_xishan@gibh.ac.cn) ; Xu, Yong(xu_yong@gibh.ac.cn) |
| 英文摘要 | Pan-BD2 inhibitors have been shown to retain an antileukemia effect and display less dose-limiting toxicities than pan-BET inhibitors. However, it is necessary to consider the potential off-target toxicity associated with the inhibition of four BET BD2 proteins. To date, no BRD4 BD2 domain selective inhibitor has been reported. Based on our previous pan-BD2 inhibitor 12 (XY153), we successfully identified 16o (XY221) as the first BRD4 BD2-selective inhibitor. 16o demonstrated potent binding affinity for BRD4 BD2 (IC50 = 5.8 nM), along with high pan-BD2 selectivity (667-fold over BRD4 BD1) and BRD4 BD2 domain selectivity (9-32-fold over BRD2/3/T BD2). The BRD4 BD2 selectivity of 16o was further confirmed by the BLI assay, showing 66-144-fold selectivity over other BET BD2 domains. 16o exhibited good liver microsomal stability (T-1/2 > 120 min) and pharmacokinetic properties (F = 13.1%). These data indicate that 16o may serve as a valuable candidate for BRD4 BD2 advancing epigenetic research. |
| WOS关键词 | HIGHLY SOLUBLE BROMO ; SELECTIVE INHIBITORS ; DOSE-ESCALATION ; BET INHIBITORS ; POTENT ; BD2 ; PROTEINS ; IDENTIFICATION ; RVX-208 ; SERIES |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001366190300001 |
| 资助机构 | State Key Laboratory of Respiratory Disease ; National Key R&D Program of China ; National Natural Science Foundation of China ; Guangdong Province Grant for Belt and Road Joint Laboratory ; State Key Laboratory of Respiratory Disease ; Youth Innovation Promotion Association CAS ; Basic Research Project of Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences ; China Postdoctoral Science Foundation ; Science and Technology Program of Guangzhou ; Guangdong Provincial Postdoctoral Special Funding ; Shanghai Advanced Research Institute, Chinese Academy of Sciences ; Guangzhou Branch of the Supercomputing Center ; Scientific Data Center of Guangzhou Institutes of Biomedicine and Health, CAS |
| 源URL | [http://ir.yic.ac.cn/handle/133337/38099]  |
| 专题 | 中国科学院烟台海岸带研究所 |
| 通讯作者 | Zhao, Linxiang; Wu, Xishan; Xu, Yong |
| 作者单位 | 1.Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China 2.Guoke Ningbo Life Sci & Hlth Ind Res Inst, Ningbo 315010, Zhejiang, Peoples R China 3.Chinese Acad Sci, Inst Drug Discovery, Guangzhou Inst Biomed & Hlth, China New Zealand Joint Lab Biomed & Hlth,Guangdon, Guangzhou 510530, Peoples R China 4.Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Anal & Testing Ctr, Guangzhou 510530, Peoples R China 5.Jilin Univ, Sch Pharmaceut Sci, Changchun 130021, Jilin, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Junhua,Hu, Qingqing,Zhu, Run,et al. Discovery of the First BRD4 Second Bromodomain (BD2)-Selective Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(23):21577-21616. |
| APA | Li, Junhua.,Hu, Qingqing.,Zhu, Run.,Dong, Ruibo.,Shen, Hui.,...&Xu, Yong.(2024).Discovery of the First BRD4 Second Bromodomain (BD2)-Selective Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,67(23),21577-21616. |
| MLA | Li, Junhua,et al."Discovery of the First BRD4 Second Bromodomain (BD2)-Selective Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY 67.23(2024):21577-21616. |
入库方式： OAI收割
来源：烟台海岸带研究所
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