Skip to main content
eScholarship
Open Access Publications from the University of California

UC San Diego

UC San Diego Previously Published Works bannerUC San Diego

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

  • Author(s): 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
  • et al.
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.

Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View