Salicylaldehyde derivatives as new protein kinase CK2 inhibitors.
Protein kinase CK2 is a Ser/Thr kinase, with a constitutive activity, that is considered as a promising target for cancer therapy. The currently available CK2 inhibitors lack the potency and the pharmacological properties necessary to be suitable and successful in clinical settings. We report the development of new potent CK2 inhibitors from salicylaldehyde derivatives identified by automated screening of a proprietary small-molecule library. Docking simulations and analysis of the structure-activity relationship for the hits allowed to determine their binding modes on CK2, and to carry out the optimization of their structures. This strategy led to the discovery of potent CK2 inhibitors with novel structures, one of which was able to inhibit CK2 activity in living cells and promote tumor cell death. The essential features required for potent CK2 inhibitory activity of this class of compounds are discussed.
Prudent
Renaud
R
INSERM, U873, Grenoble, F-38054, France; CEA, iRTSV/LTS, Grenoble, F-38054, France; Université Joseph Fourier, Grenoble, France.
López-Ramos
Miriam
M
Moucadel
Virginie
V
Barette
Caroline
C
Grierson
David
D
Mouawad
Liliane
L
Florent
Jean-Claude
JC
Lafanechère
Laurence
L
Schmidt
Frédéric
F
Cochet
Claude
C
D000447:Aldehydes / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
D000447:Aldehydes; D000970:Antineoplastic Agents; D054852:Small Molecule Libraries; C013243:salicylaldehyde; D047390:Casein Kinase II