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

DOI: 10.1038/s41598-019-52141-5 DOI Help

Authors: Irina Kufareva (University of California, San Diego) , Benoit Bestgen (Université de Lyon, Université Claude Bernard Lyon 1) , Paul Brear (University of Cambridge) , Renaud Prudent (Univ. Grenoble Alpes, Inserm U1036, CEA) , Béatrice Laudet (Univ. Grenoble Alpes, Inserm U1036, CEA) , Virginie Moucadel (Univ. Grenoble Alpes, Inserm U1036, CEA) , Mohamed Ettaoussi (Université de Lyon, Université Claude Bernard Lyon 1) , Celine F. Sautel (Univ. Grenoble Alpes, Inserm U1036, CEA) , Isabelle Krimm (Université de Lyon, CNRS, Université Claude Bernard Lyon 1) , Matthias Engel (Saarland University) , Odile Filhol (Univ. Grenoble Alpes, Inserm U1036, CEA) , Marc Le Borgne (Université de Lyon, Université Claude Bernard Lyon 1) , Thierry Lomberget (Université de Lyon, Université Claude Bernard Lyon) , Claude Cochet (Univ. Grenoble Alpes, Inserm U1036, CEA) , Ruben Abagyan (University of California)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Scientific Reports , VOL 9

State: Published (Approved)
Published: November 2019
Diamond Proposal Number(s): 18548

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.

Journal Keywords: Kinases; Molecular medicine; Target identification; Target validation; Targeted therapies

Diamond Keywords: Breast Cancer

Subject Areas: Medicine, Biology and Bio-materials, Chemistry


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 31/03/2020 10:58

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s41598-019-52141-5.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Cancer Drug Discovery Non-Communicable Diseases Structural biology Chemistry Biochemistry

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