Display Settings:

Format

Send to:

Choose Destination
J Biol Chem. 2012 Jan 6;287(2):893-904. doi: 10.1074/jbc.M111.306472. Epub 2011 Nov 18.

Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib.

Author information

  • 1Noscira S.A., Avenida de la Industria 52, 28760 Tres Cantos, Spain. jmdominguez@noscira.com

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.

PMID:
22102280
[PubMed - indexed for MEDLINE]
PMCID:
PMC3256883
Free PMC Article

Images from this publication.See all images (10)Free text

FIGURE 1.
FIGURE 2.
FIGURE 3.
SCHEME 1.
FIGURE 4.
FIGURE 5.
FIGURE 6.
FIGURE 7.
FIGURE 8.
FIGURE 9.
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk