Exploiting the Cryptic αD Pocket of Casein Kinase 2α (CK2α) to Deliver Highly Potent and Selective Type 1 Inhibitors

Casein kinase 2α (CK2α) is an oncology drug target that acts as a positive regulator of many tumorigenic signaling pathways. We previously reported that CK2α has a unique cryptic binding site, the αD pocket, that offers the potential for inhibitors with improved kinase selectivity. The prototype bivalent molecule CAM4066 (<b>6</b>) confirmed that improved selectivity could be achieved while binding in both the ATP-binding site and the αD pocket. A drug discovery project to develop a new series of bivalent CK2α inhibitors with increased cell potency and selectivity identified <b>61f</b> (APL-5125), a highly potent, ATP-competitive CK2α inhibitor with exquisite kinase selectivity and cellular potency. Compound <b>61f</b> demonstrates <i>in vivo</i> inhibition of p-AKT S129 in tumors (HCT116) following once-daily oral administration and shows a clear PK-PD relationship with unbound drug exposure. <b>61f</b> has a superior preclinical profile to existing CK2α inhibitors and is currently under evaluation in patients with advanced solid tumors.