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  3. Development of a potent BET inhibitor for the treatment of renal fibrosis

Development of a potent BET inhibitor for the treatment of renal fibrosis

  • Eur J Med Chem. 2025 Oct 5:295:117822. doi: 10.1016/j.ejmech.2025.117822.
Jianhang Huang 1,  Na Zhao 1,  Jian Li 1,  Jiayi Zhu 1,  Guoao Liang 1,  Xing Chen 1,  Naiyuan Wang 1,  Huilong Zhu 2,  Ningning Pang 3,  Chunmei An 4,  Xiaochun Xiong 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
  • 2 School of Sciences, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China.
  • 3 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China. Electronic address: pangning@xzhmu.edu.cn.
  • 4 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China. Electronic address: acmgo1988@yeah.net.
  • 5 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China. Electronic address: xiaochun.xiong@xzhmu.edu.cn.
PMID: 40449119 DOI: 10.1016/j.ejmech.2025.117822
Abstract

BRD4 serving as an attractive target for the treatment of renal fibrosis has recently received considerable attention. However, to date, the BRD4 inhibitors developed for renal fibrosis treatment were relatively few. Herein, we report the discovery of novel BRD4 inhibitors from virtual screening hit compound 1 with moderate inhibitory activity (IC50 = 7.5 ± 2.9 μM). Through the medicinal chemistry optimization program, leading to the discovery of three potent BRD4 inhibitors, 10, 19 and 31 with IC50 values of 20.0 ± 7.1, 17.5 ± 6.4 and 13.5 ± 4.9 nM, respectively. Among them, 31 showed an acceptable liver microsomal stability and displayed a desired pharmacokinetic profile. Further, we confirmed the therapeutic efficacy of 31 in alleviating renal fibrosis on both UUO and folic acid (FA)-induced renal fibrosis mouse models. Collectively, our results indicated that compound 31 might be a promising candidate for renal fibrosis treatment and deserves further investigations.

Keywords

BRD4 inhibitor; Folic acid; Quinoxaline derivatives; Renal fibrosis; Unilateral ureteral obstruction.

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