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Issue 11, 2018
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Second-generation CK2α inhibitors targeting the αD pocket

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Abstract

CK2 is a critical cell cycle regulator that also promotes various anti-apoptotic mechanisms. Development of ATP-non-competitive inhibitors of CK2 is a very attractive strategy considering that the ATP binding site is highly conserved among other kinases. We have previously utilised a pocket outside the active site to develop a novel CK2 inhibitor, CAM4066. Whilst CAM4066 bound to this new pocket it was also interacting with the ATP site: herein, we describe an example of a CK2α inhibitor that binds completely outside the active site. This second generation αD-site binding inhibitor, compound CAM4712 (IC50 = 7 μM, GI50 = 10.0 ± 3.6 μM), has numerous advantages over the previously reported CAM4066, including a reduction in the number of rotatable bonds, the absence of amide groups susceptible to the action of proteases and improved cellular permeability. Unlike with CAM4066, there was no need to facilitate cellular uptake by making a prodrug. Moreover, CAM4712 displayed no drop off between its ability to inhibit the kinase in vitro (IC50) and the ability to inhibit cell proliferation (GI50).

Graphical abstract: Second-generation CK2α inhibitors targeting the αD pocket

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Supplementary files

Article information


Submitted
01 Dec 2017
Accepted
17 Feb 2018
First published
20 Feb 2018

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2018,9, 3041-3049
Article type
Edge Article

Second-generation CK2α inhibitors targeting the αD pocket

J. Iegre, P. Brear, C. De Fusco, M. Yoshida, S. L. Mitchell, M. Rossmann, L. Carro, H. F. Sore, M. Hyvönen and D. R. Spring, Chem. Sci., 2018, 9, 3041
DOI: 10.1039/C7SC05122K

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