Selective small molecule inhibitors of glycogen synthase kinase-3 modulateglycogen metabolism and gene transcription

Background: Glycogen synthase kinase-3 (GSK-8) is a serine/threonine protei n kinase, the activity of which is inhibited by a variety of extracellular stimuli including insulin, growth factors, cell specification factors and c ell adhesion. Consequently, inhibition of GSK-3 activity has been proposed to play a role in the regulation of numerous signalling pathways that elici t pleiotropic cellular responses. This report describes the identification and characterisation of potent and selective small molecule inhibitors of G SK-3. Results: SB-216763 and SB-415286 are structurally distinct maleimides that inhibit GSK-3 alpha in vitro, with K(j)s of 9 nM and 31 nM respectively, in an ATP competitive manner. These compounds inhibited GSK-3 beta with simil ar potency. However, neither compound significantly inhibited any member of a panel of 24 other protein kinases. Furthermore, treatment of cells with either compound stimulated responses characteristic of extracellular stimul i that are known to inhibit GSK-3 activity. Thus, SB-216763 and SB-415286 s timulated glycogen synthesis in human liver cells and induced expression of a beta -catenin-LEF/TCF regulated reporter gene in HEK293 cells. In both c ases, compound treatment was demonstrated to inhibit cellular GSK-8 activit y as assessed by activation of glycogen synthase, which is a direct target of this kinase. Conclusions: SB-216763 and SB-415286 are novel, potent and selective cell p ermeable inhibitors of GSK-3. Therefore, these compounds represent valuable pharmacological tools with which the role of GSK-3 in cellular signalling can be further elucidated. Furthermore, development of similar compounds ma y be of use therapeutically in disease states associated with elevated GSK- 3 activity such as non-insulin dependent diabetes mellitus and neurodegener ative disease.