Discovery of holoenzyme-disrupting chemicals as substrate-selective CK2 inhibitors
Sautel, Celine F.
Nature Publishing Group UK
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Kufareva, I., Bestgen, B., Brear, P., Prudent, R., Laudet, B., Moucadel, V., Ettaoussi, M., et al. (2019). Discovery of holoenzyme-disrupting chemicals as substrate-selective CK2 inhibitors. Scientific Reports, 9 (1)https://doi.org/10.1038/s41598-019-52141-5
Abstract: CK2 is a constitutively active protein kinase overexpressed in numerous malignancies. Interaction between CK2α and CK2β subunits is essential for substrate selectivity. The CK2α/CK2β interface has been previously targeted by peptides to achieve functional effects; however, no small molecules modulators were identified due to pocket flexibility and open shape. Here we generated numerous plausible conformations of the interface using the fumigation modeling protocol, and virtually screened a compound library to discover compound 1 that suppressed CK2α/CK2β interaction in vitro and inhibited CK2 in a substrate-selective manner. Orthogonal SPR, crystallography, and NMR experiments demonstrated that 4 and 6, improved analogs of 1, bind to CK2α as predicted. Both inhibitors alter CK2 activity in cells through inhibition of CK2 holoenzyme formation. Treatment with 6 suppressed MDA-MB231 triple negative breast cancer cell growth and induced apoptosis. Altogether, our findings exemplify an innovative computational-experimental approach and identify novel non-peptidic inhibitors of CK2 subunit interface disclosing substrate-selective functional effects.
Article, /692/4017, /692/4028/67/1059/602, /631/92/275, /631/154/555, /631/154/556, /119/118, /145, /140/131, /82/6, /13/62, /13/95, /13/51, /96/34, /96/98, article
External DOI: https://doi.org/10.1038/s41598-019-52141-5
This record's URL: https://www.repository.cam.ac.uk/handle/1810/312379
Attribution 4.0 International (CC BY 4.0)
Licence URL: https://creativecommons.org/licenses/by/4.0/