Discovery of the First BRD4 Second Bromodomain (BD2)-Selective Inhibitors
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 <b>12</b> (XY153), we successfully identified <b>16o</b> (XY221) as the first BRD4 BD2-selective inhibitor. <b>16o</b> demonstrated potent binding affinity for BRD4 BD2 (IC<sub>50</sub> = 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 <b>16o</b> was further confirmed by the BLI assay, showing 66-144-fold selectivity over other BET BD2 domains. <b>16o</b> exhibited good liver microsomal stability (<i>T</i><sub>1/2</sub> > 120 min) and pharmacokinetic properties (<i>F</i> = 13.1%). These data indicate that <b>16o</b> may serve as a valuable candidate for BRD4 BD2 advancing epigenetic research.
Authors
- Hui Shen (ORCID: https://orcid.org/0000-0003-0335-6064)
- Jiankang Hu
- Qiuping Xiang (ORCID: https://orcid.org/0000-0002-4791-0226)
- Xishan Wu
- Bin Lin (ORCID: https://orcid.org/0000-0003-2369-4765)
- Qingqing Hu (ORCID: https://orcid.org/0000-0003-2820-9490)
- Junhua Li (ORCID: https://orcid.org/0000-0001-6466-5958)
- Xiaohan Zhang (ORCID: https://orcid.org/0000-0003-1531-3061)
- Cheng Zhang (ORCID: https://orcid.org/0000-0002-4900-231X)
- Yan Zhang (ORCID: https://orcid.org/0000-0001-5527-6360)
- Linxiang Zhao (ORCID: https://orcid.org/0000-0003-1045-5781)
- Run Zhu
- Tingting Xu (ORCID: https://orcid.org/0000-0002-1826-2012)
- Yong Xu (ORCID: https://orcid.org/0000-0003-3601-0246)
- Ruibo Dong
Institutions
- Shenyang Pharmaceutical University (CN)
- Jilin University (CN)
- Guangzhou Institutes of Biomedicine and Health (CN)
- State Key Laboratory of Respiratory Disease (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-11-27
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02516
- Citations
- 12
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 2.81
Funders
- State Key Laboratory of Respiratory Disease
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Youth Innovation Promotion Association of the Chinese Academy of Sciences
- National Key Research and Development Program of China
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences