Béatrice Laudet
Strategies for inhibiting high affinity protein-protein interaction: Example of CK2
Published on 5 October 2007
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Thesis presented October 05, 2007
Abstract:
Many arguments in favor 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 CK2α
constitutively active and a dimmer of two regulatory subunits CK2ß
. 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 protein-protein interaction. In this respect, three complementary strategies were used:
1) hot spots characterization for CK2α
-CK2ß
interaction based on tetramer crystal structure.
2) rational conception of the first antagonist of this interaction as a mimetic cyclic peptide (IC50 = 3 µM).
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.
Keywords:
CK2 protein kinase, oncology
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