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Pharmaceuticals 2017, 10(1), 16; doi:10.3390/ph10010016

In Search of Small Molecule Inhibitors Targeting the Flexible CK2 Subunit Interface

1
Biology of Cancer and Infection, INSERM, U 1036, 38054 Grenoble, France
2
Biology of Cancer and Infection, University Grenoble-Alpes (UGA), 38000 Grenoble, France
3
Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Direction de Recherche Fondamentale (DRF), Biosciences and Biotechnology Institute of Grenoble (BIG), Biology of Cancer and Infection (BCI), 38054 Grenoble, France
4
Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, 66123 Saarbrücken, Germany
5
Faculté de Pharmacie—ISPB, EA 4446 Bioactive Molecules and Medicinal Chemistry, SFR Santé Lyon-Est CNRS UMS3453—INSERM US7 Université Lyon 1, 8 avenue Rockefeller, F-69373 Lyon CEDEX 8, France
6
INSERM U 1163 / CNRS ERL 8254, Institut IMAGINE, Université Paris Descartes, 75015 Paris, France
*
Author to whom correspondence should be addressed.
Academic Editor: Joachim Jose
Received: 25 November 2016 / Revised: 16 January 2017 / Accepted: 22 January 2017 / Published: 3 February 2017
View Full-Text   |   Download PDF [3865 KB, uploaded 3 February 2017]   |  

Abstract

Protein kinase CK2 is a tetrameric holoenzyme composed of two catalytic (α and/or α’) subunits and two regulatory (β) subunits. Crystallographic data paired with fluorescence imaging techniques have suggested that the formation of the CK2 holoenzyme complex within cells is a dynamic process. Although the monomeric CK2α subunit is endowed with a constitutive catalytic activity, many of the plethora of CK2 substrates are exclusively phosphorylated by the CK2 holoenzyme. This means that the spatial and high affinity interaction between CK2α and CK2β subunits is critically important and that its disruption may provide a powerful and selective way to block the phosphorylation of substrates requiring the presence of CK2β. In search of compounds inhibiting this critical protein–protein interaction, we previously designed an active cyclic peptide (Pc) derived from the CK2β carboxy-terminal domain that can efficiently antagonize the CK2 subunit interaction. To understand the functional significance of this interaction, we generated cell-permeable versions of Pc, exploring its molecular mechanisms of action and the perturbations of the signaling pathways that it induces in intact cells. The identification of small molecules inhibitors of this critical interaction may represent the first-choice approach to manipulate CK2 in an unconventional way. View Full-Text
Keywords: protein kinase CK2; subunit interface; cyclic peptides; protein–protein interaction; cell death protein kinase CK2; subunit interface; cyclic peptides; protein–protein interaction; cell death
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MDPI and ACS Style

Bestgen, B.; Belaid-Choucair, Z.; Lomberget, T.; Le Borgne, M.; Filhol, O.; Cochet, C. In Search of Small Molecule Inhibitors Targeting the Flexible CK2 Subunit Interface. Pharmaceuticals 2017, 10, 16.

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