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 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. • XRF-1021 , a 2,4-disubstituted-5-fluoropyrimidine derivative, exhibits potent HIPK2 kinase inhibitory activity (IC 50 = 0.18 μM). • In vitro , XRF-1021 suppresses HIPK2 expression, thereby inhibiting the activation of TGF-β/Smad3, NF-κB, Wnt/β-catenin, and Notch signaling pathways. • In vivo CKD models demonstrated that XRF-1021 alleviates renal injury and attenuates renal fibrosis, supporting its potential as a HIPK2 inhibitor. • XRF-1021 shows favorable pharmacokinetic characteristics, good metabolic stability, low systemic toxicity, and promising druggability.