Identification of CK2α' selective inhibitors by the screening of an allosteric-kinase-inhibitor-like compound library
Protein Kinase CK2 is a holoenzyme composed of two regulatory subunits (CK2{beta}) and two catalytic subunits (CK2 and CK2). CK2 controls several cellular processes including proliferation, inflammation, and cell death. However, CK2 and CK2 possess different expression patterns and substrates and therefore impact each of these processes differently. Elevated CK2 participates in the development of cancer, while increased CK2 has been associated with neurodegeneration, especially Huntingtons disease (HD). HD is a fatal disease for which no effective therapies are available. Genetic deletion of CK2 in HD mouse models has ameliorated neurodegeneration. Therefore, pharmacological inhibition of CK2 presents a promising therapeutic strategy for treating HD. However, current CK2 inhibitors are unable to discriminate between CK2 and CK2 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 CK2 that contained different residues than CK2 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 CK2 activity-dependent ADP-GloTM Kinase assay. Obtained hits were counter-screened against CK2 revealing two CK2 selective compounds. These two compounds might serve as the basis for further medicinal chemistry optimization for the potential treatment of HD.