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 (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.