Expanding the chemical diversity of CK2 inhibitors.
None of the already described CK2 inhibitors did fulfill the requirements for successful clinical settings. In order to find innovative CK2 inhibitors based on new scaffolds, we have performed a high-throughput screening of diverse chemical libraries. We report here the identification and characterization of several classes of new inhibitors. Whereas some share characteristics of previously known CK2 inhibitors, others are chemically unrelated and may represent new opportunities for the development of better CK2 inhibitors. By combining structure-activity relationships with a docking procedure, we were able to determine the binding mode of these inhibitors. Interestingly, beside the identification of several nanomolar ATP-competitive inhibitors, one class of chemical inhibitors displays a non-ATP competitive mode of inhibition, a feature that suggests that CK2 possess distinct druggable binding sites. For the most promising inhibitors, selectivity profiling was performed. We also provide evidence that some chemical compounds are inhibiting CK2 in living cells. Finally, the collected data allowed us to draw the rules about the chemical requirements for CK2 inhibition both in vitro and in a cellular context.
INSERM, U873, Grenoble, 38054, France.
Renaud
R
Prudent
Virginie
V
Moucadel
Miriam
M
López-Ramos
Samia
S
Aci
Beatrice
B
Laudet
Liliane
L
Mouawad
Caroline
C
Barette
Jacques
J
Einhorn
Cathy
C
Einhorn
Jean-Noel
JN
Denis
Gilles
G
Bisson
Frédéric
F
Schmidt
Sylvaine
S
Roy
Laurence
L
Lafanechere
Jean-Claude
JC
Florent
Claude
C
Cochet
D001681:Biological Assay; D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D006801:Humans; D008958:Models, Molecular; D010797:Phthalimides / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013379:Substrate Specificity / Q000187:drug effects; D013844:Thiazoles / Q000737:chemistry; D014966:Xanthenes / Q000737:chemistry
D010797:Phthalimides; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D013844:Thiazoles; D014966:Xanthenes; D047390:Casein Kinase II