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

Irina Kufareva (1) , Benoît Bestgen (2) , Paul Brear (3) , Renaud Prudent (4) , Béatrice Laudet (5) , Virginie Moucadel (5) , Mohamed Ettaoussi (6) , Céline Sautel (4) , Isabelle Krimm (7) , Matthias Engel (8) , Odile Filhol (9) , Marc Le Borgne (2) , Thierry Lomberget (2) , Claude Cochet (9) , Ruben Abagyan (1)

1 Skaggs School of Pharmacy and Pharmaceutical Sciences [San Diego]
2 B2MC - Molécules bioactives et chimie médicinale
3 CAM - University of Cambridge [UK]
4 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
5 BCI - Biologie du Cancer et de l'Infection
6 JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837
7 CRMN - Centre de Résonance Magnetique Nucleaire
8 Saarland University [Saarbrücken]
9 IMAC - Invasion mechanisms in angiogenesis and cancer

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.

Domaines: Pharmacologie; Médicaments; Chimie thérapeutique; Biologie structurale [q-bio.BM]

Irina Kufareva, Benoît Bestgen, Paul Brear, Renaud Prudent, Béatrice Laudet, et al.. Discovery of holoenzyme-disrupting chemicals as substrate-selective CK2 inhibitors. Scientific Reports, 2019, 9 (1), pp.15893. ⟨10.1038/s41598-019-52141-5⟩. ⟨hal-02348673⟩