title: 5-imino-1,2,4-thiadiazoles: first small molecules as substrate competitive inhibitors of glycogen synthase kinase 3.
abstract: 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 site.
authors.affiliation: Instituto de Química Médica-CSIC, Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Valle
authors.initials: V
authors.lastname: Palomo
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Perez
authors.forename: Concepcion
authors.initials: C
authors.lastname: Perez
authors.forename: Jose A
authors.initials: JA
authors.lastname: Morales-Garcia
authors.forename: Ignacio
authors.initials: I
authors.lastname: Soteras
authors.forename: Sandra
authors.initials: S
authors.lastname: Alonso-Gil
authors.forename: Arantxa
authors.initials: A
authors.lastname: Encinas
authors.forename: Ana
authors.initials: A
authors.lastname: Castro
authors.forename: Nuria E
authors.initials: NE
authors.lastname: Campillo
authors.forename: Ana
authors.initials: A
authors.lastname: Perez-Castillo
authors.forename: Carmen
authors.initials: C
authors.lastname: Gil
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008567:Membranes, Artificial; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009573:Nitrites / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013552:Swine; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007097:Imines; D008070:Lipopolysaccharides; D008567:Membranes, Artificial; D018696:Neuroprotective Agents; D009573:Nitrites; D013830:Thiadiazoles; D038362:Glycogen Synthase Kinase 3