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Béatrice Laudet

Strategies for inhibiting high affinity protein-protein interaction: Example of CK2

Published on 5 October 2007


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 CK2
α 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 understandi​ng 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 CK2
α-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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