Inhibiting CK2α from Outside the Active Site

EKJ is a highly conserved kinase with pro survival and anti-apoptotic effects on cells. It is often overexpressed in cancer cells in which it promotes their proliferation by multiple mechanisms. A number of potent CK2a inhibitors,B that target only the ATP site, have been shown to inhibit the growth of a range of cancer cell lines and one of these, CX-4945 has progressed to phase II clinical trials. Although described as highly selective, CX-4945 inhibits at least 12 other kinases with nanomolar IC50's.

Strategies to inhibit CK2a without targeting the ATP binding site offer the promise of enhanced selectivity as well as new mechanisms of action. Here we report the creation and characterization of a unique inhibitor of CK2a that targets a novel cryptic pocket and was developed using fragment-based methods.