title: Identification of polyoxometalates as nanomolar noncompetitive inhibitors of protein kinase CK2.
abstract: 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.
authors.affiliation: Laboratoire de Transduction du Signal, Institut de Recherche en Technologies et Sciences pour le Vivant, CEA, 17 Rue des Martyrs 38054 Grenoble, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Prudent
authors.forename: Virginie
authors.initials: V
authors.lastname: Moucadel
authors.forename: Béatrice
authors.initials: B
authors.lastname: Laudet
authors.forename: Caroline
authors.initials: C
authors.lastname: Barette
authors.forename: Laurence
authors.initials: L
authors.lastname: Lafanechère
authors.forename: Bernold
authors.initials: B
authors.lastname: Hasenknopf
authors.forename: Joaquim
authors.initials: J
authors.lastname: Li
authors.forename: Sébastian
authors.initials: S
authors.lastname: Bareyt
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Lacôte
authors.forename: Serge
authors.initials: S
authors.lastname: Thorimbert
authors.forename: Max
authors.initials: M
authors.lastname: Malacria
authors.forename: Pierre
authors.initials: P
authors.lastname: Gouzerh
authors.forename: Claude
authors.initials: C
authors.lastname: Cochet
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D001665:Binding Sites; D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017973:Tungsten Compounds / Q000737:chemistry / Q000494:pharmacology*; D000099294:Polyoxometalates
chemical_list: D000255:Adenosine Triphosphate; D047390:Casein Kinase II; D010455:Peptides; D047428:Protein Kinase Inhibitors; D017973:Tungsten Compounds; C102296:polyoxometalate I; D000099294:Polyoxometalates