Discovery of XRF-1021, a 2,4-disubstituted-5-fluoropyrimidine derivative as a homeodomain-interacting protein kinase 2 inhibitor for the treatment of chronic kidney disease

  • Eur J Med Chem. 2026 Jan 15;302(Pt 2):118353. doi: 10.1016/j.ejmech.2025.118353.
Xinlan Hu  1 ,  Songkai Wang  2 ,  Songsen Fu  1 ,  Jianhua Zeng  2 ,  Yan Wu  1 ,  Li Gong  2 ,  Yuanyuan Cao  1 ,  Yan Zhang  2 ,  Yuanyuan Han  2 ,  Hanyi Ouyang  1 ,  Yiwei Xiong  2 ,  Xin He  2 ,  Jiawei Cheng  2 ,  Sijue Zou  2 ,  Zhuo Chen  1 ,  Lijian Tao  3 ,  Jie Meng  4 ,  Ling Huang  3 ,  Qiongjing Yuan  3 ,  Zhangzhe Peng  5 ,  Qianbin Li  6
Affiliations
  • 1. Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Small Molecules for Diagnosis and Treatment of Chronic Disease, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Changsha, 410013, Hunan, China.
  • 2. Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, 410013, Hunan, China; FuRong Laboratory, Changsha, 410078, Hunan, China.
  • 3. Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, 410013, Hunan, China; FuRong Laboratory, Changsha, 410078, Hunan, China; National International Collaborative Research Centre for Medical Metabolomics, Xiangya Hospital, Central South University, Changsha, 410008, China.
  • 4. Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, 410013, Hunan, China; FuRong Laboratory, Changsha, 410078, Hunan, China; National International Collaborative Research Centre for Medical Metabolomics, Xiangya Hospital, Central South University, Changsha, 410008, China; Department of Pulmonary and Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
  • 5. Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, 410013, Hunan, China; FuRong Laboratory, Changsha, 410078, Hunan, China; National International Collaborative Research Centre for Medical Metabolomics, Xiangya Hospital, Central South University, Changsha, 410008, China. Electronic address: [email protected].
  • 6. Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Small Molecules for Diagnosis and Treatment of Chronic Disease, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Changsha, 410013, Hunan, China. Electronic address: [email protected].
PMID: 41207211 DOI: 10.1016/j.ejmech.2025.118353
Abstract

Homeodomain-interacting protein kinase 2 (HIPK2) has been identified as a promising therapeutic target for chronic kidney disease. In this study, a series of 2,4-disubstituted-5-fluoropyrimidine derivatives were designed and synthesized. Kinase assay and cell proliferation screening results showed that compound 7a (XRF-1021) demonstrated potent HIPK2 inhibitory activity (IC50 = 0.18 μM). 7a reduced the expression of fibrotic markers in TGF-β1 stimulated NRK-49F and HK-2 cells, including Fibronectin, Collagen I and α-SMA. In vivo, 7a significantly improved renal function in models with 0.2 % adenine diet and unilateral ureteral obstruction (UUO), reducing tubular injury and Collagen deposition. These results suggest that 7a is a promising candidate for the development of targeted anti-fibrotic therapies, offering a novel approach to treating chronic kidney disease.

Keywords
Anti-fibrotic therapy; HIPK2; Renal fibrosis; XRF-1021.
Products