Discovery of a Potent and Selective Naphthyridine-Based Chemical Probe for Casein Kinase 2
Zachary W. Davis‐Gilbert, Andreas Krämer, James E. Dunford, Stefanie Howell, Filiz Senbabaoglu, Carrow I. Wells, Frances M. Bashore, Tammy M. Havener, Jeffery L. Smith, Mohammad Anwar Hossain, Udo Oppermann, David H. Drewry, Alison D. Axtman
Abstract
High Resolution Image Download MS PowerPoint Slide Naphthyridine-based inhibitors were synthesized to yield a potent and cell-active inhibitor of casein kinase 2 (CK2). Compound 2 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 ( 7 ) was designed on the basis of structural studies. Compound 7 does not bind CK2α or CK2α′ in cells and demonstrates excellent kinome-wide selectivity. Differential anticancer 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 with which to interrogate biology mediated by CK2.