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dc.contributor.authorBrear, Paulen
dc.contributor.authorBall, Darbyen
dc.contributor.authorStott, Katherineen
dc.contributor.authorD'Arcy, Sheenaen
dc.contributor.authorHyvönen, Markoen
dc.date.accessioned2020-10-16T23:30:23Z
dc.date.available2020-10-16T23:30:23Z
dc.date.issued2020-11en
dc.identifier.issn0022-2623
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/311630
dc.description.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>
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherAmerican Chemical Society
dc.rightsAll rights reserved
dc.rights.uri
dc.subjectHumansen
dc.subjectNaphthyridinesen
dc.subjectCasein Kinase IIen
dc.subjectRecombinant Proteinsen
dc.subjectAdenosine Triphosphateen
dc.subjectProtein Kinase Inhibitorsen
dc.subjectLigandsen
dc.subjectCrystallography, X-Rayen
dc.subjectDeuterium Exchange Measurementen
dc.subjectNuclear Magnetic Resonance, Biomolecularen
dc.subjectAllosteric Regulationen
dc.subjectAllosteric Siteen
dc.subjectBinding, Competitiveen
dc.subjectProtein Bindingen
dc.subjectMolecular Dynamics Simulationen
dc.titleProposed Allosteric Inhibitors Bind to the ATP Site of CK2α.en
dc.typeArticle
prism.endingPage12798
prism.issueIdentifier21en
prism.publicationDate2020en
prism.publicationNameJournal of medicinal chemistryen
prism.startingPage12786
prism.volume63en
dc.identifier.doi10.17863/CAM.58720
dcterms.dateAccepted2020-10-15en
rioxxterms.versionofrecord10.1021/acs.jmedchem.0c01173en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2020-11en
dc.contributor.orcidBrear, Paul [0000-0002-4045-0474]
dc.contributor.orcidStott, Katherine [0000-0002-4014-1188]
dc.contributor.orcidD'Arcy, Sheena [0000-0001-5055-988X]
dc.contributor.orcidHyvönen, Marko [0000-0001-8683-4070]
dc.identifier.eissn1520-4804
rioxxterms.typeJournal Article/Reviewen
cam.orpheus.successThu Nov 05 11:51:07 GMT 2020 - Embargo updated*
cam.orpheus.counter3*
rioxxterms.freetoread.startdate2021-10-29


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