Issue 11, 2016

Specific inhibition of CK2α from an anchor outside the active site


The development of selective inhibitors of protein kinases is challenging because of the significant conservation of the ATP binding site. Here, we describe a new mechanism by which the protein kinase CK2α can be selectively inhibited using features outside the ATP site. We have identified a new binding site for small molecules on CK2α adjacent to the ATP site and behind the αD loop, termed the αD pocket. An elaborated fragment anchored in this site has been linked with a low affinity fragment binding in the ATP site, creating a novel and selective inhibitor (CAM4066) that binds CK2α with a Kd of 320 nM and shows significantly improved selectivity compared to other CK2α inhibitors. CAM4066 shows target engagement in several cell lines and similar potency to clinical trial candidate CX4945. Our data demonstrate that targeting a poorly conserved, cryptic pocket allows inhibition of CK2α via a novel mechanism, enabling the development of a new generation of selective CK2α inhibitors.

Graphical abstract: Specific inhibition of CK2α from an anchor outside the active site

Supplementary files

Article information

Article type
Edge Article
25 May 2016
10 Jul 2016
First published
12 Jul 2016
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2016,7, 6839-6845

Specific inhibition of CK2α from an anchor outside the active site

P. Brear, C. De Fusco, K. Hadje Georgiou, N. J. Francis-Newton, C. J. Stubbs, H. F. Sore, A. R. Venkitaraman, C. Abell, D. R. Spring and M. Hyvönen, Chem. Sci., 2016, 7, 6839 DOI: 10.1039/C6SC02335E

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