Stratégies pour inhiber une interaction protéine-protéine de haute affinité : l'exemple de la protéine kinase CK2

Abstract : Many arguments in favour of oncogenic potential of CK2 protein kinase make it a promising therapeutic target in oncology. This protein kinase is composed of a tetrameric complex of two catalytic subunits CK2a constitutively active and a dimmer of two regulatory subunits CK2b. Our laboratory showed that dynamic interaction between these two subunits in cell is an essential component for this enzyme regulation. For better understanding this regulation in normal and pathologic processes, it seems necessary to develop compounds able to perturb this proteinprotein interaction. In this respect, three complementary strategies were used: 1) hot spots characterization for CK2a-CK2b interaction based on tetramer crystal structure. 2) rational conception of the first antagonist of this interaction as a mimetic cyclic peptide (IC50 = 3 mM). 3) pharmacophore definition based on this peptide allowing to identify chemical molecules analogs by virtual screening. A cluster of chemical compounds active as well in vitro as in vivo has been identified. They represent the first inhibitors for this interaction.
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Contributor : Béatrice Laudet <>
Submitted on : Saturday, August 19, 2017 - 6:45:19 PM
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Béatrice Laudet. Stratégies pour inhiber une interaction protéine-protéine de haute affinité : l'exemple de la protéine kinase CK2. Biologie structurale [q-bio.BM]. UJF Grenoble-1, 2007. Français. ⟨tel-01575407⟩

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