Evidence for Irreversible Inhibition of Glycogen Synthase Kinase-3β by Tideglusib

Abstract

Background: Tideglusib is a GSK-3 inhibitor currently undergoing clinical trials for Alzheimer disease and progressive supranuclear palsy. Results: Removal of unbound compound does not recover the enzyme activity, and the dissociation rate constant is close to zero. The protein shows a low turnover rate in neurons. Conclusion: Tideglusib is an irreversible inhibitor of GSK-3␤. Significance: The irreversibility and the long enzyme half-life may possess interesting pharmacodynamic implications.

Allosteric Noncompetitive Small Molecule Selective Inhibitors of CD45 Tyrosine Phosphatase Suppress T-Cell Receptor Signals and Inflammation In Vivo

“…There are precedents in which an allosteric inhibitor irreversibly destabilizes an enzyme via a nonoxidative mechanism (Piver et al, 2001;Ucar et al, 2005;Domínguez et al, 2012).…”

Diaminothiazoles Modify Tau Phosphorylation and Improve the Tauopathy in Mouse Models*

“…Four brain slices were selected from each animal, at regular intervals and spanning the anterior to posterior portions of the hippocampus. For the PHF-1 and ␥H2AX staining, slices were treated with 50 mM NH 4 Cl for 10 min at RT, preincubated with 0.1% Triton X-100, 1% BSA, PBS for 1 h. Sections were double- stained by incubation with PHF-1 and ␥H2AX antibodies at 4°C for 3 days; Alexa 488 anti-rabbit and Alexa 594 anti-mouse were used as secondary fluorescent probes and incubated an additional day in the presence of Hoechst 33342 (Calbiochem) to fluorescently label cell nuclei. Slices were mounted in microscopy glass slices using FluorSave mounting media (Calbiochem).…”

“…The brains of patients with Alzheimer disease (AD) 4 undergo extensive cell death and are histopathologically characterized by both plaques containing amyloid-␤ protein and neurofibrillary tangles (NFTs) containing hyperphosphorylated Tau protein. Therapeutic strategies directed toward the NFTs are few and remain unproven.…”

Tau Diagnostics and Clinical Studies

“…It is possible that drug administration was too late in the disease process, and unable to reverse previously accumulated cell damage. An additional previous failure was with the GSK-3 inhibitor tideglusib (Dominguez et al 2012), for example, in AD (del del Ser et al 2013) and PSP (Tolosa et al 2014). Interestingly, while there were no physical or behavioral benefits for tideglusib, it did reduce progression of brain atrophy .…”