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

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Bestgen, Benoit 
Brear, Paul 
Prudent, Renaud 
Laudet, Béatrice 


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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U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) (GM117424, GM074832)
Agence Nationale de la Recherche (French National Research Agency) (PCV08_324733)
NHLBI NIH HHS (R35 HL135737)
NIGMS NIH HHS (R01 GM074832, R01 GM117424)
Institut National Du Cancer (French National Cancer Institute) (No 57, 2011-097)
NIAID NIH HHS (R01 AI118985)
NINDS NIH HHS (R01 NS102432)
U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID) (AI118985)
Région Auvergne-Rhône-Alpes (Region Auvergne-Rhône-Alpes) (ARC 1 Santé 12-008707-01)