{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:44:44Z","timestamp":1768509884657,"version":"3.49.0"},"posted":{"date-parts":[[2024,1,22]]},"group-title":"Biochemistry","reference-count":73,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,1,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Protein Kinase CK2 is a holoenzyme composed of two regulatory subunits (CK2\u03b2) and two catalytic subunits (CK2\u03b1 and CK2\u03b1\u2019). CK2 controls several cellular processes including proliferation, inflammation, and cell death. However, CK2\u03b1 and CK2\u03b1\u2019 possess different expression patterns and substrates and therefore impact each of these processes differently. Elevated CK2\u03b1 participates in the development of cancer, while increased CK2\u03b1\u2019 has been associated with neurodegeneration, especially Huntington\u2019s disease (HD). HD is a fatal disease for which no effective therapies are available. Genetic deletion of CK2\u03b1\u2019 in HD mouse models has ameliorated neurodegeneration. Therefore, pharmacological inhibition of CK2\u03b1\u2019 presents a promising therapeutic strategy for treating HD. However, current CK2 inhibitors are unable to discriminate between CK2\u03b1 and CK2\u03b1\u2019 due to their high structural homology, especially in the targeted ATP binding site. Using computational analyses, we found a potential Type IV (\u201cD\u201d pocket) allosteric site on CK2\u03b1\u2019 that contained different residues than CK2\u03b1 and was distal from the ATP binding pocket featured in both kinases. With this potential allosteric site in mind, we screened a commercial library containing \u223c29,000 allosteric-kinase-inhibitor-like compounds using a CK2\u03b1\u2019 activity-dependent ADP-Glo\n                  <jats:sup>TM<\/jats:sup>\n                  Kinase assay. Obtained hits were counter-screened against CK2\u03b1 revealing two CK2\u03b1\u2019 selective compounds. These two compounds might serve as the basis for further medicinal chemistry optimization for the potential treatment of HD.\n                <\/jats:p>","DOI":"10.1101\/2024.01.18.576328","type":"posted-content","created":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T06:50:18Z","timestamp":1705906218000},"source":"Crossref","is-referenced-by-count":0,"title":["Identification of CK2\u03b1\u2019 selective inhibitors by the screening of an allosteric-kinase-inhibitor-like compound library"],"prefix":"10.64898","author":[{"given":"Deepti","family":"Mudaliar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel H.","family":"Mansky","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8039-3542","authenticated-orcid":false,"given":"Angel","family":"White","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grace","family":"Baudhuin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5461-7071","authenticated-orcid":false,"given":"Jon","family":"Hawkinson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1755-1485","authenticated-orcid":false,"given":"Henry","family":"Wong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5650-9277","authenticated-orcid":false,"given":"Michael A.","family":"Walters","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1136-5462","authenticated-orcid":false,"given":"Rocio","family":"Gomez-Pastor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"issue":"2","key":"2024012322301755000_2024.01.18.576328v1.1","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/S0021-9258(18)71184-8","article-title":"The enzymatic phosphorylation of proteins","volume":"211","year":"1954","journal-title":"J Biol Chem"},{"key":"2024012322301755000_2024.01.18.576328v1.2","doi-asserted-by":"publisher","DOI":"10.1042\/bj20021469"},{"key":"2024012322301755000_2024.01.18.576328v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-381298-8.00023-X"},{"key":"2024012322301755000_2024.01.18.576328v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELL.2020.06.034"},{"key":"2024012322301755000_2024.01.18.576328v1.5","doi-asserted-by":"crossref","unstructured":"Castello, J. , et al., CK2-An Emerging Target for Neurological and Psychiatric Disorders. Pharmaceuticals (Basel), 2017. 10(1).","DOI":"10.3390\/ph10010007"},{"key":"2024012322301755000_2024.01.18.576328v1.6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0115609"},{"key":"2024012322301755000_2024.01.18.576328v1.7","doi-asserted-by":"crossref","unstructured":"Chen, Y. , et al., Strategies of Targeting CK2 in Drug Discovery: Challenges, Opportunities, and Emerging Prospects. J Med Chem, 2023.","DOI":"10.1021\/acs.jmedchem.2c01523"},{"key":"2024012322301755000_2024.01.18.576328v1.8","doi-asserted-by":"publisher","DOI":"10.1021\/jm101251q"},{"key":"2024012322301755000_2024.01.18.576328v1.9","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2015.00070"},{"key":"2024012322301755000_2024.01.18.576328v1.10","doi-asserted-by":"crossref","unstructured":"Ferrer-Font, L. , et al., Targeting Protein Kinase CK2: Evaluating CX-4945 Potential for GL261 Glioblastoma Therapy in Immunocompetent Mice. Pharmaceuticals (Basel), 2017. 10(1).","DOI":"10.3390\/ph10010024"},{"key":"2024012322301755000_2024.01.18.576328v1.11","doi-asserted-by":"crossref","unstructured":"FDA, CX-4945 Granted Orphan Drug Designation 2017: Oncology Times. p. 23.","DOI":"10.1097\/01.COT.0000514203.35081.69"},{"key":"2024012322301755000_2024.01.18.576328v1.12","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-1893"},{"key":"2024012322301755000_2024.01.18.576328v1.13","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-8-29"},{"issue":"2","key":"2024012322301755000_2024.01.18.576328v1.14","first-page":"263","article-title":"Casein kinase II alteration precedes tau accumulation in tangle formation","volume":"140","year":"1992","journal-title":"Am.J.Pathol"},{"key":"2024012322301755000_2024.01.18.576328v1.15","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M312760200"},{"issue":"1","key":"2024012322301755000_2024.01.18.576328v1.16","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s12974-015-0470-x","article-title":"Increased occurrence of protein kinase CK2 in astrocytes in Alzheimer\u2019s disease pathology","volume":"13","year":"2016","journal-title":"J.Neuroinflammation"},{"issue":"3","key":"2024012322301755000_2024.01.18.576328v1.17","doi-asserted-by":"crossref","first-page":"e90452","DOI":"10.1371\/journal.pone.0090452","article-title":"Casein kinase II induced polymerization of soluble TDP-43 into filaments is inhibited by heat shock proteins","volume":"9","year":"2014","journal-title":"PLoS.One"},{"key":"2024012322301755000_2024.01.18.576328v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14405"},{"key":"2024012322301755000_2024.01.18.576328v1.19","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.3.975-987.2003"},{"key":"2024012322301755000_2024.01.18.576328v1.20","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.19.5320"},{"key":"2024012322301755000_2024.01.18.576328v1.21","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.00074"},{"key":"2024012322301755000_2024.01.18.576328v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/12729"},{"key":"2024012322301755000_2024.01.18.576328v1.23","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01119-07"},{"key":"2024012322301755000_2024.01.18.576328v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/srep42409"},{"key":"2024012322301755000_2024.01.18.576328v1.25","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-017-2705-8"},{"key":"2024012322301755000_2024.01.18.576328v1.26","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-011-0963-6"},{"key":"2024012322301755000_2024.01.18.576328v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2012.11.013"},{"key":"2024012322301755000_2024.01.18.576328v1.28","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-1314"},{"key":"2024012322301755000_2024.01.18.576328v1.29","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-011-0959-2"},{"key":"2024012322301755000_2024.01.18.576328v1.30","doi-asserted-by":"crossref","first-page":"14405","DOI":"10.1038\/ncomms14405","article-title":"Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington\u2019s disease","volume":"8","year":"2017","journal-title":"Nature Communications"},{"key":"2024012322301755000_2024.01.18.576328v1.31","doi-asserted-by":"crossref","unstructured":"Yu, D. , et al., CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington\u2019s disease. 2022, Bio Med Central: Acta Neuropathologica Communications.","DOI":"10.1186\/s40478-022-01379-8"},{"key":"2024012322301755000_2024.01.18.576328v1.32","doi-asserted-by":"crossref","unstructured":"White, A. , A. McGlone , and R. Gomez-Pastor , Protein Kinase CK2 and Its Potential Role as a Therapeutic Target in Huntington\u2019s Disease. Biomedicines, 2022. 10(8).","DOI":"10.3390\/biomedicines10081979"},{"key":"2024012322301755000_2024.01.18.576328v1.33","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.025668"},{"key":"2024012322301755000_2024.01.18.576328v1.34","doi-asserted-by":"crossref","first-page":"824956","DOI":"10.3389\/fnmol.2022.824956","article-title":"Evaluation of a Selective Chemical Probe Validates That CK2 Mediates Neuroinflammation in a Human Induced Pluripotent Stem Cell-Derived Mircroglial Model","volume":"15","year":"2022","journal-title":"Front Mol Neurosci"},{"key":"2024012322301755000_2024.01.18.576328v1.35","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2018.00146"},{"key":"2024012322301755000_2024.01.18.576328v1.36","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E12-12-0903"},{"key":"2024012322301755000_2024.01.18.576328v1.37","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2018.00146"},{"key":"2024012322301755000_2024.01.18.576328v1.38","doi-asserted-by":"publisher","DOI":"10.1039\/d1ob00257k"},{"issue":"4","key":"2024012322301755000_2024.01.18.576328v1.39","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/j.chembiol.2020.12.013","article-title":"Development of a potent and selective chemical probe for the pleiotropic kinase CK2","volume":"28","year":"2021","journal-title":"Cell Chem Biol"},{"issue":"3","key":"2024012322301755000_2024.01.18.576328v1.40","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.bbapap.2009.09.003","article-title":"Structure-based discovery of small molecules targeting different surfaces of protein-kinase CK2","volume":"1804","year":"2010","journal-title":"Biochim Biophys Acta"},{"issue":"6","key":"2024012322301755000_2024.01.18.576328v1.41","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1074\/mcp.M700559-MCP200","article-title":"An unbiased evaluation of CK2 inhibitors by chemoproteomics: characterization of inhibitor effects on CK2 and identification of novel inhibitor targets","volume":"7","year":"2008","journal-title":"Mol.Cell Proteomics"},{"issue":"8","key":"2024012322301755000_2024.01.18.576328v1.42","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1021\/ml400197u","article-title":"Structure and Property Based Design of Pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 Kinase with Activity in Vivo","volume":"4","year":"2013","journal-title":"ACS Med Chem Lett"},{"issue":"4","key":"2024012322301755000_2024.01.18.576328v1.43","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1021\/ml200257n","article-title":"Potent and Selective Inhibitors of CK2 Kinase Identified through Structure-Guided Hybridization","volume":"3","year":"2012","journal-title":"ACS Med Chem Lett"},{"key":"2024012322301755000_2024.01.18.576328v1.44","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.19.5320"},{"issue":"2","key":"2024012322301755000_2024.01.18.576328v1.45","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1021\/acs.jmedchem.0c02076","article-title":"Structure\u2013 and Similarity-Based Survey of Allosteric Kinase Inhibitors, Activators, and Closely Related Compounds","volume":"65","year":"2022","journal-title":"J Med Chem"},{"issue":"21","key":"2024012322301755000_2024.01.18.576328v1.46","doi-asserted-by":"crossref","first-page":"12786","DOI":"10.1021\/acs.jmedchem.0c01173","article-title":"Proposed Allosteric Inhibitors Bind to the ATP Site of CK2\u03b1","volume":"63","year":"2020","journal-title":"J Med Chem"},{"issue":"6","key":"2024012322301755000_2024.01.18.576328v1.47","doi-asserted-by":"crossref","first-page":"2899","DOI":"10.1021\/jm2015167","article-title":"Structure-based design of novel potent protein kinase CK2 (CK2) inhibitors with phenyl-azole scaffolds","volume":"55","year":"2012","journal-title":"J Med Chem"},{"issue":"1-2","key":"2024012322301755000_2024.01.18.576328v1.48","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s11010-017-3228-1","article-title":"Inhibitory influence of natural flavonoids on human protein kinase CK2 isoforms: effect of the regulatory subunit","volume":"444","year":"2018","journal-title":"Mol Cell Biochem"},{"issue":"3","key":"2024012322301755000_2024.01.18.576328v1.49","doi-asserted-by":"crossref","first-page":"5471","DOI":"10.1021\/acsomega.8b03415","article-title":"Diacritic Binding of an Indenoindole Inhibitor by CK2\u03b1 Paralogs Explored by a Reliable Path to Atomic Resolution CK2\u03b1\u2019 Structures","volume":"4","year":"2019","journal-title":"ACS Omega"},{"key":"2024012322301755000_2024.01.18.576328v1.50","doi-asserted-by":"publisher","DOI":"10.1021\/jm901137j"},{"key":"2024012322301755000_2024.01.18.576328v1.51","doi-asserted-by":"publisher","DOI":"10.1089\/adt.2009.0222"},{"key":"2024012322301755000_2024.01.18.576328v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4889(90)90098-X"},{"key":"2024012322301755000_2024.01.18.576328v1.53","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.82.3.737"},{"key":"2024012322301755000_2024.01.18.576328v1.54","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1994.1128"},{"key":"2024012322301755000_2024.01.18.576328v1.55","doi-asserted-by":"publisher","DOI":"10.1002\/9781118540398"},{"key":"2024012322301755000_2024.01.18.576328v1.56","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-008-9770-1"},{"key":"2024012322301755000_2024.01.18.576328v1.57","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2017"},{"key":"2024012322301755000_2024.01.18.576328v1.58","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.9b00214"},{"issue":"19","key":"2024012322301755000_2024.01.18.576328v1.59","doi-asserted-by":"crossref","first-page":"9136","DOI":"10.1016\/S0021-9258(18)48058-1","article-title":"Substrate specificity determinants for casein kinase II as deduced from studies with synthetic peptides","volume":"262","year":"1987","journal-title":"J Biol Chem"},{"key":"2024012322301755000_2024.01.18.576328v1.60","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-4838(99)00147-8"},{"key":"2024012322301755000_2024.01.18.576328v1.61","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1995.1024"},{"key":"2024012322301755000_2024.01.18.576328v1.62","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(95)01542-6"},{"key":"2024012322301755000_2024.01.18.576328v1.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2009.01.013"},{"issue":"2","key":"2024012322301755000_2024.01.18.576328v1.64","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1515\/bmc.2010.013","article-title":"Variable contribution of protein kinases to the generation of the human phosphoproteome: a global weblogo analysis","volume":"1","year":"2010","journal-title":"Biomol Concepts"},{"key":"2024012322301755000_2024.01.18.576328v1.65","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.29.18640"},{"issue":"1","key":"2024012322301755000_2024.01.18.576328v1.66","doi-asserted-by":"crossref","first-page":"e15976","DOI":"10.1371\/journal.pone.0015976","article-title":"Deciphering human heat shock transcription factor 1 regulation via post-translational modification in yeast","volume":"6","year":"2011","journal-title":"PLoS.One"},{"issue":"3","key":"2024012322301755000_2024.01.18.576328v1.67","doi-asserted-by":"crossref","first-page":"112198","DOI":"10.1016\/j.celrep.2023.112198","article-title":"Tumor suppressor p53 regulates heat shock factor 1 protein degradation in Huntington\u2019s disease","volume":"42","year":"2023","journal-title":"Cell Rep"},{"key":"2024012322301755000_2024.01.18.576328v1.68","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.3149"},{"key":"2024012322301755000_2024.01.18.576328v1.69","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20170189"},{"key":"2024012322301755000_2024.01.18.576328v1.70","doi-asserted-by":"publisher","DOI":"10.1021\/cb400771y"},{"key":"2024012322301755000_2024.01.18.576328v1.71","doi-asserted-by":"publisher","DOI":"10.1021\/bi300531c"},{"key":"2024012322301755000_2024.01.18.576328v1.72","doi-asserted-by":"publisher","DOI":"10.1021\/cb300054n"},{"key":"2024012322301755000_2024.01.18.576328v1.73","doi-asserted-by":"publisher","DOI":"10.1021\/jm050540c"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.01.18.576328","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T05:49:12Z","timestamp":1768456152000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.01.18.576328"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,22]]},"references-count":73,"URL":"https:\/\/doi.org\/10.1101\/2024.01.18.576328","relation":{},"subject":[],"published":{"date-parts":[[2024,1,22]]},"subtype":"preprint"}}