Paul Brear, Darby Ball, Katherine Stott, Sheena D’Arcy and Marko Hyvönen
Journal of Medicinal Chemistry: 63, 21, 12786–12798 (2020)
DOI: 0.1021/acs.jmedchem.0c01173
PDB coordinates:
6YPH (3D view),6YPK (3D view),6YPJ (3D view),6YPN (3D view)
Abstract
CK2α is a ubiquitous, well-studied 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. Comparison of our results and experimental approach with the data presented in the original report suggest the primary reason for the disparity is non-specific inhibition by aggregation