A molecular perspective for the use of type IV tyrosine kinase inhibitors as anticancer therapeutics

Das, Rudradip; Choithramani, Asmita; Shard, Amit

doi:10.1016/j.drudis.2021.12.009

Cited by 5 publications

(1 citation statement)

References 66 publications

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“…A type IV site is a site remote from the ATP site that is prone to allosteric modulation . There is ample evidence for type IV allosteric inhibitors to impact kinase activity in a lot of kinases. ,, Although the mode of action of type IV inhibitors may vary, including structural reorganization of the ATP-binding pocket, prevention of active complex formation, prevention of substrate recognition, stabilization of inactive complexes, or induction of degradation, they all result in the overall depletion of kinase activity, and some can decrease ATP binding. , To identify new CK2α′ hits that could potentially target this type IV allosteric site, we decided to screen a commercial library of 28,812 allosteric-kinase-inhibitor-like compounds (the ChemDiv Allosteric Kinase Inhibitor (CDAKI) Library). This library is a focused collection of compounds from the ChemDiv compound collection, structurally based on known allosteric kinase inhibitors and their analogues.…”

Section: Resultsmentioning

confidence: 99%

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

Mudaliar,

Mansky,

White

et al. 2024

ACS Chem. Neurosci.

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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.

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