2. Academic Validation
  3. 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

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

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.

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