5-imino-1,2,4-thiadiazoles: first small molecules as substrate competitive inhibitors of glycogen synthase kinase 3

Cumulative evidence strongly supports that glycogen synthase kinase-3 (GSK-3) is a pathogenic molecule when it is up-dysregulated, emerging as an important therapeutic target in severe unmet human diseases. GSK-3 specific inhibitors might be promising effective drugs for the treatment of devastating pathologies such as neurodegenerative diseases, stroke, and mood disorders. As GSK-3 has the ability to phosphorylate primed substrates, small molecules able to bind to this site should be perfect drug candidates, able to partially block the activity of the enzyme over some specific substrates. Here, we report substituted 5-imino-1,2,4-thiadiazoles as the first small molecules able to inhibit GSK-3 in a substrate competitive manner. These compounds are cell permeable, able to decrease inflammatory activation and to selectively differentiate neural stem cells. Overall, 5-imino-1,2,4-thiadiazoles are presented here as new molecules able to decrease neuronal cell death and to increase endogenous neurogenesis blocking the GSK-3 substrate siteWe gratefully acknowledge the financial support of Ministry of Science and Innovation (MICINN, projects no. SAF2009-13015-C02-01, to A.M. and SAF2010-16365, to A.P-C.), and FECYT, project no. INC-0367, to A.M.) and Instituto de Salud Carlos III (ISCiii, project no. RD07/0060/0015). V.P. and D.I.P. acknowledge pre- and postdoctoral fellowships respectively from CSIC (JAE program).Peer Reviewe