ArticleThe Journal of biological chemistry2012
Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 112 papers.
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Who cites it
112 citing papers in PubMed, 225 citations in OpenAlex.
- Design, synthesis and antiproliferative activity of oxadiazole derivatives as potent glycogen synthase kinase-3/histone deacetylase 6 dual inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2026Article
- Intestinal epithelial GSK3β governs fumarate-dependent neutrophil reprogramming to promote colorectal cancer.Nature cancer · 2026Article
- Targeting the BACE1-GSK-3β Signaling Axis in Alzheimer's Disease: From Molecular Crosstalk to Nanotechnology-Based Translational Strategies.Molecular neurobiology · 2026Review
- Current Landscape of Glycogen Synthase Kinase-3β PET Tracers: Progress, Limitations, and Perspectives-A Narrative Review.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Selective Brain-Penetrant TTBK1 Inhibitors Modulate TDP-43 Pathology and Rescue Cognitive Deficits in a Mouse Model of TDP-43 Proteinopathy.Journal of medicinal chemistry · 2026Article
- Injectable GSK3 inhibitor (Tideglusib) hydrogel versus enhanced β-tricalcium phosphate in tibial bone healing (in vitro and in vivo study).Odontology · 2026Article
- Glycogen Synthase Kinase-3β Inhibition Ameliorates Synaptic and Mitochondrial Dysfunction in a Sporadic Alzheimer's Disease-Like Model.Molecular neurobiology · 2026Article
- Targeting of kinases to treat neurodegenerative diseases.Pharmacological reviews · 2026Review
- Network-Guided Identification of Plant-Derived Modulators of Stress-Adaptive Signalling in Neuroblastoma.International journal of molecular sciences · 2026Article
- Protein kinases as therapeutic targets in Alzheimer's disease: challenges, insights, and new frontiers.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Review
- Brain Permeable SGK1 Inhibitors: A Promising Therapeutic Strategy for Neurodegenerative Diseases.Journal of medicinal chemistry · 2026Article
- Tideglusib-Preactivated Osteoblasts Encapsulated in Ceramic Particle-Reinforced GelMA Hydrogel for Enhanced Critical-Size Bone Defect Regeneration.Drug design, development and therapy · 2026Article
- Role of GSK-3 Inhibition in Alzheimer's Disease Therapy.Current Alzheimer research · 2026Review
- Progress on novel compounds for the treatment of bone metabolism-related disorders: focus on osteoporosis and beyond.Frontiers in chemistry · 2026Review
- The cross-talk between GSK-3β, RKIP, and PTEN as potential targets for therapeutic implications in cancer: a comprehensive insight.Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques · 2026Review
- Advances in the treatment of Alzheimer's disease.Frontiers in pharmacology · 2026Review
- Lithium restores inhibitory function and neuronal excitability through GSK-3β inhibition in a bipolar disorder-associated Ank3 variant mouse model.Neuropharmacology · 2025Article
- Computational identification of phytochemicals as glycogen synthase kinase 3 beta (GSK3β) inhibitors for therapeutic applications in chronic diseases.Scientific reports · 2025Article
- Regenerative Medicine in the Treatment of Alzheimer's Disease: A Narrative Review.Iranian journal of public health · 2025Review
- Article
52 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.