The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
Evidence for Irreversible Inhibition of Glycogen Synthase Kinase-3β by Tideglusib
Open accessAbstract
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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Cites
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
Haass, C., & Selkoe, D. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2101 · Cited by 4,744
The resurgence of covalent drugs
Singh, J., Petter, R. C., Baillie, T. A., & Whitty, A. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3410 · Cited by 1,873
Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer's Disease Mouse Models
Ittner, L. M., Ke, Y. D., Delerue, F., Bi, M., Gladbach, A., van Eersel, J., Wölfing, H., Chieng, B. C., Christie, M. J., Napier, I. A., et al. (2010) · Cell · doi:10.1016/j.cell.2010.06.036 · Cited by 1,821
The GSK3 hypothesis of Alzheimer’s disease
Hooper, C., Killick, R., & Lovestone, S. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.05194.x · Cited by 1,191
Blalock, E. M., Geddes, J. W., Chen, K. C., Porter, N. M., Markesbery, W. R., & Landfield, P. W. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308512100 · Cited by 1,025
Ring, D. B., Johnson, K. W., Henriksen, E. J., Nuss, J. M., Goff, D., Kinnick, T. R., Ma, S. T., Reeder, J. W., Samuels, I., Slabiak, T., et al. (2003) · Diabetes · doi:10.2337/diabetes.52.3.588 · Cited by 532
Ishiguro, K., Shiratsuchi, A., Sato, S., Omori, A., Arioka, M., Kobayashi, S., Uchida, T., & Imahori, K. (1993) · FEBS Letters · doi:10.1016/0014-5793(93)81066-9 · Cited by 402
GSK3: a possible link between beta amyloid peptide and tau protein
Hernández, F., Gómez de Barreda, E., Fuster-Matanzo, A., Lucas, J. J., & Avila, J. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2009.09.011 · Cited by 327
Association of GSK3B with Alzheimer disease and frontotemporal dementia
Schaffer, B. A. J., Bertram, L., Miller, B. L., Mullin, K., Weintraub, S., Johnson, N., Bigio, E. H., Mesulam, M., Wiedau-Pazos, M., Jackson, G. R., et al. (2008) · Archives of Neurology · doi:10.1001/archneur.65.10.1368 · Cited by 100
Mateo, I., Infante, J., Llorca, J., Rodríguez, E., Berciano, J., & Combarros, O. (2006) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000091044 · Cited by 53
Cited by
Tau pathology and neurodegeneration
Spillantini, M. G., & Goedert, M. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70090-5 · Cited by 1,133
Tau-targeting therapies for Alzheimer disease
Congdon, E. E., & Sigurdsson, E. M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0013-z · Cited by 1,113
Targeting hepatic glucose metabolism in the treatment of type 2 diabetes
Rines, A. K., Sharabi, K., Tavares, C. D. J., & Puigserver, P. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.151 · Cited by 375
A phase 2 trial of the GSK‐3 inhibitor tideglusib in progressive supranuclear palsy
Tolosa, E., Litvan, I., Höglinger, G. U., Burn, D., Lees, A., Andrés, M. V., Gómez‐Carrillo, B., León, T., del Ser, T., & for the TAUROS Investigators (2014) · Movement Disorders · doi:10.1002/mds.25824 · Cited by 320
Advances in covalent kinase inhibitors
Abdeldayem, A., Raouf, Y. S., Constantinescu, S. N., Moriggl, R., & Gunning, P. T. (2020) · Chemical Society Reviews · doi:10.1039/c9cs00720b · Cited by 317
Metadata
- Authors
- Domínguez, J. M., Fuertes, A., Orozco, L., del Monte-Millán, M., Delgado, E., & Medina, M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 287
- Issue
- 2
- Pages
- 893-904
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2003159754
- Cited by
- 246
- References
- 10
- FWCI
- 5.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Domínguez, J. M., Fuertes, A., Orozco, L., del Monte-Millán, M., Delgado, E., & Medina, M. (2012). Evidence for Irreversible Inhibition of Glycogen Synthase Kinase-3β by Tideglusib. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m111.306472
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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