Proposed Allosteric Inhibitors Bind to the ATP Site of CK2α.
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Publication Date
2020-11Journal Title
Journal of medicinal chemistry
ISSN
0022-2623
Publisher
American Chemical Society
Volume
63
Issue
21
Pages
12786-12798
Language
eng
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Brear, P., Ball, D., Stott, K., D'Arcy, S., & Hyvönen, M. (2020). Proposed Allosteric Inhibitors Bind to the ATP Site of CK2α.. Journal of medicinal chemistry, 63 (21), 12786-12798. https://doi.org/10.1021/acs.jmedchem.0c01173
Abstract
<jats:title>Abstract</jats:title><jats:p>CK2α is a ubiquitous, well-studied protein kinase that is a target for small molecule inhibition, for treatment of cancers. While many different classes of ATP-competitive inhibitors have been described for CK2α, they tend to suffer from significant off-target activity and new approaches are needed. A series of inhibitors of CK2α has recently been described as allosteric, acting at a previously unidentified binding site. Given the similarity of these inhibitors to known ATP-competitive inhibitors, we have investigated these further. In our thorough structural and biophysical analyses, we have found no evidence that these inhibitors bind to the proposed allosteric site. Rather, we report crystal structures, competitive ITC and NMR, HDX mass spectrometry and chemoinformatic analyses that all point to these compounds binding in the ATP pocket. Our crystal structures however do show that the proposed allosteric site can bind ligands, just not those in the previously described series. Comparison of our results and experimental details with the data presented in the original report suggest several reasons for the disparity in our conclusions, the primary reason being non-specific inhibition by aggregation.</jats:p><jats:sec id="s5"><jats:title>Table of Content graphics</jats:title><jats:fig id="ufig1" position="float" fig-type="figure" orientation="portrait"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="191353v2_ufig1" position="float" orientation="portrait" /></jats:fig></jats:sec>
Keywords
Humans, Naphthyridines, Casein Kinase II, Recombinant Proteins, Adenosine Triphosphate, Protein Kinase Inhibitors, Ligands, Crystallography, X-Ray, Deuterium Exchange Measurement, Nuclear Magnetic Resonance, Biomolecular, Allosteric Regulation, Allosteric Site, Binding, Competitive, Protein Binding, Molecular Dynamics Simulation
Embargo Lift Date
2021-10-29
Identifiers
External DOI: https://doi.org/10.1021/acs.jmedchem.0c01173
This record's URL: https://www.repository.cam.ac.uk/handle/1810/311630
Rights
All rights reserved