Discovery of a CK2α′-Biased ATP-Competitive Inhibitor from a High-Throughput Screen of an Allosteric-Inhibitor-Like Compound Library

• Published in: ACS chemical neuroscience 2024-08, Vol.15 (15), p.2703-2718
• Main Authors: Mudaliar, Deepti, Mansky, Rachel H., White, Angel, Baudhuin, Grace, Hawkinson, Jon, Wong, Henry, Walters, Michael A., Gomez-Pastor, Rocio
• Format: Article
• Language: English
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.4c00062

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 that contained different residues between CK2α and CK2α′ and was distal from the ATP-binding pocket featured in both kinases. We decided to look for allosteric modulators that might interact in a biased fashion with the type IV pocket on both CK2α and CK2α′. 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 using the ADP-Glo Kinase assay, revealing two CK2α′-biased compounds. These two compounds might serve as the basis for further medicinal chemistry optimization for the potential treatment of HD.