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

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 (IC<sub>50</sub> = 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.

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Publication Details

Journal
European Journal of Medicinal Chemistry
Published
2025-11-07
DOI
https://doi.org/10.1016/j.ejmech.2025.118353
Citations
1
Primary Topic
Chronic Kidney Disease and Diabetes
Type
article
Field-Weighted Citation Impact
1.43
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article

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

Yiwei Xiong, Xin He, Yan Wu, Hanyi Ouyang et al.
1 citations
European Journal of Medicinal Chemistry
Chronic Kidney Disease and Diabetes
1.43
article

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

Yiwei Xiong, Xin He, Yan Wu, Hanyi Ouyang, Li Gong, Songkai Wang, Ling Huang, Yuanyuan Han, Zhangzhe Peng, Jiawei Cheng, Yuanyuan Cao, Qiongjing Yuan, Zhuo Chen, Yan Zhang, Lijian Tao, Jianhua Zeng, Jie Meng, Qianbin Li, Xinlan Hu, Songsen Fu, Sijue Zou
article en
1 citations

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 (IC<sub>50</sub> = 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.

European Journal of Medicinal ChemistryVol. 302(Pt 2)
Central South University (CN), Hunan University (CN), Third Xiangya Hospital (CN), Xiangya Hospital Central South University (CN)
Openalex Percentile: Top 14%
Chronic Kidney Disease and Diabetes
1.43
DOIOpen Access PDFOpenAlex
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