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 replaceme

SUBMITTER: Dominguez JM 

PROVIDER: S-EPMC3256883 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature