Discovery of KDX1381, a Bivalent CK2α Inhibitor for the Treatment of Solid Tumors as a Single Agent or in Combination

Casein kinase 2 (CK2) has emerged as a promising therapeutic target across a broad spectrum of malignancies, including pediatric and orphan cancers. The identification of a ligandable allosteric αD pocket on the CK2α subunit has enabled the development of bivalent inhibitors, which bind simultaneously to both the adenosine triphosphate (ATP) site and the allosteric pocket. Here, we report the discovery and pharmacological characterization of KDX1381, a structure-guided bivalent CK2α inhibitor with low-nanomolar potency and high selectivity, confirmed by cocrystal structures. In mice, KDX1381 suppressed CK2-driven tumor growth as a monotherapy and enhanced therapeutic efficacy when combined with vascular endothelial growth factor receptor (VEGFR) inhibitors or DNA-damaging agents in hepatocellular carcinoma and glioma models. These findings support bivalent CK2α inhibition as a differentiated therapeutic strategy with broad applicability in CK2-dependent cancers.