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 2 selectively inhibits CK2⍺ and CK2⍺’ when profiled broadly, making it an exquisitely selective chemical probe for CK2. A negative control that is structurally related but lacks a key hinge-binding nitrogen (7) was designed based on structural studies. Compound 7 does not bind CK2⍺ or CK2⍺’ in cells and demonstrates excellent kinome-wide selectivity. Differential anti-cancer activity was observed when compound 2 was profiled alongside a structurally distinct CK2 chemical probe: SGC-CK2-1. This naphthyridine-based chemical probe (2) represents one of the best available small molecule tools to interrogate biology mediated by CK2.


Supplementary material

Supporting Information
Chemistry, biological evaluation, and crystallographic methods. Spectra for key compounds.