Identification of polyoxometalates as nanomolar noncompetitive inhibitors of protein kinase CK2.
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.
Prudent
Renaud
R
Laboratoire de Transduction du Signal, Institut de Recherche en Technologies et Sciences pour le Vivant, CEA, 17 Rue des Martyrs 38054 Grenoble, France.
Moucadel
Virginie
V
Laudet
Béatrice
B
Barette
Caroline
C
Lafanechère
Laurence
L
Hasenknopf
Bernold
B
Li
Joaquim
J
Bareyt
Sébastian
S
Lacôte
Emmanuel
E
Thorimbert
Serge
S
Malacria
Max
M
Gouzerh
Pierre
P
Cochet
Claude
C
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
D000255:Adenosine Triphosphate; D047390:Casein Kinase II; D010455:Peptides; D047428:Protein Kinase Inhibitors; D017973:Tungsten Compounds; C102296:polyoxometalate I; D000099294:Polyoxometalates