6YPG

Proposed Allosteric Inhibitors Bind to the ATP Site of CK2 alpha.

(2020) J Med Chem 63: 12786-12798

• PubMed: 33119282 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1021/acs.jmedchem.0c01173
• Primary Citation of Related Structures:  
  6YPG, 6YPH, 6YPJ, 6YPK, 6YPN


• PubMed 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 adenosine 5'-triphosphate (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 them 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 isothermal titration calorimetry (ITC) and NMR, hydrogen-deuterium exchange (HDX) mass spectrometry, and chemoinformatic analyses that all point to these compounds binding in the ATP pocket. Comparisons of our results and experimental approach with the data presented in the original report suggest that the primary reason for the disparity is nonspecific inhibition by aggregation.

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Organizational Affiliation: 

Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, U.K.