Identification of polyoxometalates as nanomolar noncompetitive inhibitors of protein kinase CK2.

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Prudent, Renaud | Moucadel, Virginie | Laudet, Béatrice | Barette, Caroline | Lafanechère, Laurence | Hasenknopf, Bernold | Li, Joaquim | Bareyt, Sébastian | Lacôte, Emmanuel | Thorimbert, Serge | Malacria, Max | Gouzerh, Pierre | Cochet, Claude

Edité par CCSD -

International audience. Protein kinase CK2 is a multifunctional kinase of medical importance that is dysregulated in many cancers. In this study, polyoxometalates were identified as original CK2 inhibitors. [P2Mo18O62](6-) has the most potent activity. It inhibits the kinase in the nanomolar range by targeting key structural elements located outside the ATP- and peptide substrate-binding sites. Several polyoxometalate derivatives exhibit strong inhibitory efficiency, with IC50 values < or = 10 nM. Furthermore, these inorganic compounds show a striking specificity for CK2 when tested in a panel of 29 kinases. Therefore, polyoxometalates are effective CK2 inhibitors in terms of both efficiency and selectivity and represent nonclassical kinase inhibitors that interact with CK2 in a unique way. This binding mode may provide an exploitable mechanism for developing potent drugs with desirable properties, such as enhanced selectivity relative to ATP-mimetic inhibitors.

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