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Discovery of holoenzyme-disrupting chemicals as substrate-selective CK2 inhibitors

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 modulat...

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Detalles Bibliográficos
Autores principales: Kufareva, Irina, Bestgen, Benoit, Brear, Paul, Prudent, Renaud, Laudet, Béatrice, Moucadel, Virginie, Ettaoussi, Mohamed, Sautel, Celine F., Krimm, Isabelle, Engel, Matthias, Filhol, Odile, Borgne, Marc Le, Lomberget, Thierry, Cochet, Claude, Abagyan, Ruben
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828666/
https://www.ncbi.nlm.nih.gov/pubmed/31685885
http://dx.doi.org/10.1038/s41598-019-52141-5
Descripción
Sumario: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.