Key imidazolyl groups that induce phenylalanine flipping enhance the efficacy of oral BRD9 inhibitors for AML treatment

https://doi.org/10.1016/j.apsb.2025.08.006

This new article publication from Acta Pharmaceutica Sinica B, discusses how key imidazolyl groups that induce phenylalanine flipping enhance the efficacy of oral BRD9 inhibitors for AML treatment.

The bromodomain-containing protein 9 (BRD9) is a core subunit of mammalian SWI/SNF chromatin remodeling complex termed ncBAF. BRD9 has emerged as a potential target for anticancer drugs, particularly in the treatment of acute myeloid leukemia (AML). The authors of this article report 10m (Y22073) and 10t as new BRD9 selective bromodomain inhibitors. Crystallographic studies revealed that the key active imidazolyl group discovered from structure-activity relationship (SAR) can induce Phe163 flipping and significantly enhance the cellular potency of the compounds, making 10m the first BRD9 selective inhibitor with significant cellular activity against AML cells. The critical role of imidazolyl groups were also validated by modifying existing BRD9 inhibitors. The representative compounds 10m and 10t demonstrated potent binding affinity, outstanding selectivity toward BRD9 bromodomain, and significantly inhibited the proliferation of AML cell lines. 10m also showed good metabolic stability, solubility and pharmacokinetic properties. Additionally, oral administration of compounds 10m and 10t exhibited potent anti-tumor efficacy in the MV4-11 xenograft mouse model. The potent, selective, and orally available BRD9 bromodomain inhibitors may address the challenges of weak cellular activity and limited phenotypic efficacy faced by BRD9 inhibitors, and serve as new lead compounds for the development of anticancer agents for the treatment of AML.

Keywords: Epigenetics, Bromodomain, BRD9 inhibitor, Drug design, Structure optimization, Crystallographic study, Imidazolyl group, Acute myeloid leukemia

Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383525005544-ga1_lrg.jpg

Crystallographic studies revealed that the imidazolyl group can induce Phe163 flipping and significantly enhance the cellular potency of the compounds, making 10m (Y22073) the best-ever BRD9 selective inhibitor in vivo.

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The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association.

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CiteScore: 24.3

Impact Factor: 14.6 (Top 6 journal in the category of Pharmacology and pharmacy) 

JIF without self-citation: 13.8

ISSN 2211-3835

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Zhiming Chen, Cheng Zhang, Hui Shen, Hongrui Xu, Yumin Huang, Ruibo Dong, Xin Tang, Shuang Chai, Junhua Li, Jinxin Xu, Xiaohan Zhang, Yan Zhang, Xishan Wu, Yong Xu, Key imidazolyl groups that induce phenylalanine flipping enhance the efficacy of oral BRD9 inhibitors for AML treatment, Acta Pharmaceutica Sinica B, Volume 15, Issue 12, 2025, Pages 6546-6570, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2025.08.006