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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.

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.

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