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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.date.accessioned2020-11-03T18:28:24Z
dc.date.available2020-11-03T18:28:24Z
dc.date.issued2019-11-04
dc.date.submitted2019-05-15
dc.identifier.others41598-019-52141-5
dc.identifier.other52141
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/312379
dc.description.abstractAbstract: 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.
dc.languageen
dc.publisherNature Publishing Group UK
dc.rightsAttribution 4.0 International (CC BY 4.0)en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectArticle
dc.subject/692/4017
dc.subject/692/4028/67/1059/602
dc.subject/631/92/275
dc.subject/631/154/555
dc.subject/631/154/556
dc.subject/119/118
dc.subject/145
dc.subject/140/131
dc.subject/82/6
dc.subject/13/62
dc.subject/13/95
dc.subject/13/51
dc.subject/96/34
dc.subject/96/98
dc.subjectarticle
dc.titleDiscovery of holoenzyme-disrupting chemicals as substrate-selective CK2 inhibitors
dc.typeArticle
dc.date.updated2020-11-03T18:22:37Z
prism.issueIdentifier1
prism.publicationNameScientific Reports
prism.volume9
dc.identifier.doi10.17863/CAM.59471
dcterms.dateAccepted2019-10-07
rioxxterms.versionofrecord10.1038/s41598-019-52141-5
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
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]
dc.identifier.eissn2045-2322


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