title: Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib.
abstract: Tideglusib is a GSK-3 inhibitor currently in phase II clinical trials for the treatment of Alzheimer disease and progressive supranuclear palsy. Sustained oral administration of the compound to a variety of animal models decreases Tau hyperphosphorylation, lowers brain amyloid plaque load, improves learning and memory, and prevents neuronal loss. We report here that tideglusib inhibits GSK-3β irreversibly, as demonstrated by the lack of recovery in enzyme function after the unbound drug has been removed from the reaction medium and the fact that its dissociation rate constant is non-significantly different from zero. Such irreversibility may explain the non-competitive inhibition pattern with respect to ATP shown by tideglusib and perhaps other structurally related compounds. The replacement of Cys-199 by an Ala residue in the enzyme seems to increase the dissociation rate, although the drug retains its inhibitory activity with decreased potency and long residence time. In addition, tideglusib failed to inhibit a series of kinases that contain a Cys homologous to Cys-199 in their active site, suggesting that its inhibition of GSK-3β obeys to a specific mechanism and is not a consequence of nonspecific reactivity. Results obtained with [(35)S]tideglusib do not support unequivocally the existence of a covalent bond between the drug and GSK-3β. The irreversibility of the inhibition and the very low protein turnover rate observed for the enzyme are particularly relevant from a pharmacological perspective and could have significant implications on its therapeutic potential.
authors.affiliation: Noscira S.A., Avenida de la Industria 52, 28760 Tres Cantos, Spain. jmdominguez@noscira.com
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Domínguez
authors.forename: Ana
authors.initials: A
authors.lastname: Fuertes
authors.forename: Leyre
authors.initials: L
authors.lastname: Orozco
authors.forename: María
authors.initials: M
authors.lastname: del Monte-Millán
authors.forename: Elena
authors.initials: E
authors.lastname: Delgado
authors.forename: Miguel
authors.initials: M
authors.lastname: Medina
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D000818:Animals; D002460:Cell Line; D017322:Clinical Trials, Phase II as Topic; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018411:Spodoptera; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
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