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
Year: 2025
Type: article
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 50 = 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.
Authors: Xinlan Hu, Songkai Wang, Songsen Fu, Jianhua Zeng, Yan Wu, Li Gong, Yuanyuan Cao, Yan Zhang, Yuanyuan Han, Hanyi Ouyang, Yiwei Xiong, Xin He, Jiawei Cheng, Sijue Zou, Zhuo Chen, Lijian Tao, Jie Meng, Ling Huang, Qiongjing Yuan, Zhangzhe Peng, Qianbin Li
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: hybrid
Estimated APC paid: $4,650
OpenAlex ID: W4416009291