Abstract
Protein Kinase CK2 is a holoenzyme composed of two regulatory subunits (CK2β) and two catalytic subunits (CK2α and CK2α'). CK2 controls several cellular processes including proliferation, inflammation, and cell death. However, CK2α and CK2α' possess different expression patterns and substrates and therefore impact each of these processes differently. Elevated CK2α participates in the development of cancer, while increased CK2α' has been associated with neurodegeneration, especially Huntington's disease (HD). HD is a fatal disease for which no effective therapies are available. Genetic deletion of CK2α' in HD mouse models has ameliorated neurodegeneration. Therefore, pharmacological inhibition of CK2α' presents a promising therapeutic strategy for treating HD. However, current CK2 inhibitors are unable to discriminate between CK2α and CK2α' due to their high structural homology, especially in the targeted ATP binding site. Using computational analyses, we found a potential Type IV ("D" pocket) allosteric site on CK2α' that contained different residues than CK2α 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 ~29,000 allosteric-kinase-inhibitor-like compounds using a CK2α' activity-dependent ADP-Glo™ Kinase assay. Obtained hits were counter-screened against CK2α revealing two CK2α' selective compounds. These two compounds might serve as the basis for further medicinal chemistry optimization for the potential treatment of HD.