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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Bibliographic Details
Published in:Scientific reports 2019-11, Vol.9 (1), p.15893-16, Article 15893
Main Authors: 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
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Apoptosis
Binding Sites
Biochemistry, Molecular Biology
Breast cancer
Casein Kinase II - antagonists & inhibitors
Casein Kinase II - metabolism
Catalytic Domain
Cell Line, Tumor
Cell Movement - drug effects
Cell Proliferation - drug effects
Chemical Sciences
Computer applications
Crystallography
Crystallography, X-Ray
Fumigation
Holoenzymes - chemistry
Holoenzymes - metabolism
Humans
Kinases
Kinetics
Life Sciences
Medication
Medicinal Chemistry
Molecular Docking Simulation
NMR
Nuclear magnetic resonance
Peptides - chemistry
Peptides - metabolism
Pharmaceutical sciences
Pharmacology
Phosphorylation
Protein kinase
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - metabolism
Protein Kinase Inhibitors - pharmacology
Protein structure
Protein Subunits - antagonists & inhibitors
Protein Subunits - metabolism
Structural Biology
Substrate Specificity
Surface Plasmon Resonance
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-52141-5