Scaffold hopping and sidechain modification from a flavone scaffold lead to discovery of potent, selective CK2A2 inhibitors with favorable properties for CNS activity.

The human protein kinase CK2 has long been of interest as a target in oncology, but new evidence is emerging of its role in central nervous system (CNS) disorders. The CK2 catalytic subunit paralog CK2A2 is enriched in the CNS relative to other tissues; however, the catalytic subunit paralog CK2A1 is expressed at similar levels across most tissues. Current treatment modalities centered on CK2 inhibition under clinical study lack evidence of CNS activity, kinome-wide selectivity, or CK2A2 paralog selectivity. Therefore, a brain-penetrant inhibitor selective for CK2A2 over CK2A1 may enable the further elucidation of the role of this paralog in CNS pathologies. In this work, we describe a series of flavone-inspired inhibitors of CK2A1 and CK2A2 designed and synthesized in a structure-based drug-design campaign. Multiple candidates demonstrating promising CK2A2 potency, kinome-wide selectivity, and CNS permeability/activity were identified, with compound 65 representing the best confluence of these properties. Although these lead candidates exhibited only up to three-fold preferential inhibition of CK2A2, they represent a starting point for the study of CK2A2 and the disorders it may mediate in the CNS.