Discovery of a Potent and Selective Naphthyridine-Based Chemical Probe for Casein Kinase 2.

Naphthyridine-based inhibitors were synthesized to yield a potent and cell-active inhibitor of casein kinase 2 (CK2). Compound selectively inhibits CK2α and CK2α' when profiled broadly, thereby making it an exquisitely selective chemical probe for CK2. A negative control that is structurally related but lacks a key hinge-binding nitrogen () was designed on the basis of structural studies. Compound does not bind CK2α or CK2α' in cells and demonstrates excellent kinome-wide selectivity. Differential anticancer activity was observed when compound was profiled alongside a structurally distinct CK2 chemical probe: SGC-CK2-1. This naphthyridine-based chemical probe () represents one of the best available small molecule tools with which to interrogate biology mediated by CK2.