Structural and Mechanistic Basis of the Inhibitory Potency of Selected 2-Aminothiazole Compounds on Protein Kinase CK2

Lindenblatt, D.; Nickelsen, Anna; Applegate, Violetta; Jose, Joachim; Niefind, Karsten

doi:10.1021/acs.jmedchem.0c00587

Cited by 12 publications

(15 citation statements)

References 47 publications

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“…While we were preparing this manuscript for publication, the Niefind group published their analysis of the same series of compounds, which also showed binding to the ATP site by X-ray crystallography. 65 While they have not done other biophysical analyses on the binding, they do show by the enzymatic assay that these inhibitors are ATP competitive, consistent with our data. One of the cornerstones of the theory of allosteric inhibition was the observation that CX4945 binds CK2α simultaneously with 1, and that 1 competes with inositol hexaphosphate (IP 6 , phytic acid), shown by mass spectrometry.…”

Section: ■ Discussionsupporting

confidence: 89%

“…This evidence included: competitive native mass spectroscopy studies, ligand-based NMR, thermal shift analysis, and biochemical assays. While we were preparing this manuscript for publication, the Niefind group published their analysis of the same series of compounds, which also showed binding to the ATP site by X-ray crystallography . While they have not done other biophysical analyses on the binding, they do show by the enzymatic assay that these inhibitors are ATP competitive, consistent with our data.…”

Section: Discussionsupporting

confidence: 82%

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Proposed Allosteric Inhibitors Bind to the ATP Site of CK2α

et al. 2020

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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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Section: ■ Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 82%

Proposed Allosteric Inhibitors Bind to the ATP Site of CK2α

et al. 2020

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show abstract

Section: Discussionsupporting

confidence: 89%

Proposed allosteric inhibitors bind to the ATP site of CK2α

Brear

Ball

Stott

et al. 2020

Preprint

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AbstractCK2α 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.

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“…104 Independently, Lindenblatt et al also obtained co-crystal structures of these compounds with CK2 showing binding to the ATP site and used kinase enzyme assay to demonstrate that these inhibitors do indeed act via an ATP-competitive mechanism. 105 Modulators of the CK2β subunit Lastly, another approach to inhibit CK2 outside its catalytic pocket is to interact with the CK2β subunit.…”

Section: Inhibitors Of Ck2α Acting Outside the Atp Pocketmentioning

confidence: 99%