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dc.contributor.authorKufareva, Irina
dc.contributor.authorBestgen, Benoit
dc.contributor.authorBrear, Paul
dc.contributor.authorPrudent, Renaud
dc.contributor.authorLaudet, Béatrice
dc.contributor.authorMoucadel, Virginie
dc.contributor.authorEttaoussi, Mohamed
dc.contributor.authorSautel, Celine F
dc.contributor.authorKrimm, Isabelle
dc.contributor.authorEngel, Matthias
dc.contributor.authorFilhol, Odile
dc.contributor.authorBorgne, Marc Le
dc.contributor.authorLomberget, Thierry
dc.contributor.authorCochet, Claude
dc.contributor.authorAbagyan, Ruben
dc.description.abstractCK2 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.
dc.rightsAttribution 4.0 International
dc.sourcenlmid: 101563288
dc.sourceessn: 2045-2322
dc.titleDiscovery of holoenzyme-disrupting chemicals as substrate-selective CK2 inhibitors.
dc.contributor.orcidKufareva, Irina [0000-0001-9083-7039]
dc.contributor.orcidFilhol, Odile [0000-0003-1964-7958]
dc.contributor.orcidBorgne, Marc Le [0000-0003-1398-075X]
pubs.funder-project-idU.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) (GM117424, GM074832)
pubs.funder-project-idAgence Nationale de la Recherche (French National Research Agency) (PCV08_324733)
pubs.funder-project-idNHLBI NIH HHS (R35 HL135737)
pubs.funder-project-idNIGMS NIH HHS (R01 GM074832, R01 GM117424)
pubs.funder-project-idInstitut National Du Cancer (French National Cancer Institute) (No 57, 2011-097)
pubs.funder-project-idNIAID NIH HHS (R01 AI118985)
pubs.funder-project-idNINDS NIH HHS (R01 NS102432)
pubs.funder-project-idU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID) (AI118985)
pubs.funder-project-idRégion Auvergne-Rhône-Alpes (Region Auvergne-Rhône-Alpes) (ARC 1 Santé 12-008707-01)

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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International