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.
Prudent
Renaud
R
INSERM, U873, Grenoble, 38054, France.
Moucadel
Virginie
V
López-Ramos
Miriam
M
Aci
Samia
S
Laudet
Beatrice
B
Mouawad
Liliane
L
Barette
Caroline
C
Einhorn
Jacques
J
Einhorn
Cathy
C
Denis
Jean-Noel
JN
Bisson
Gilles
G
Schmidt
Frédéric
F
Roy
Sylvaine
S
Lafanechere
Laurence
L
Florent
Jean-Claude
JC
Cochet
Claude
C
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