GSK-3 Inhibitors for the Treatment of Alzheimer's Disease

Bhat, Ratan V.; Berg, Stefan von; Burrows, Jeremy N.; Lindquist, Johanna M.

doi:10.1007/7355_2007_015

Cited by 7 publications

(8 citation statements)

References 96 publications

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“…Bhat and colleagues from AstraZeneca have written a very comprehensive review on GSK3 inhibitors for the treatment of AD and readers are encouraged to refer to this review for details about the various inhibitor classes. In this review we will briefly outline these classes of inhibitors (69). …”

Section: Gsk3 Inhibitorsmentioning

confidence: 99%

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Tau as a Therapeutic Target for Alzheimers Disease

Boutajangout¹,

Sigurdsson²,

Krishnamurthy³

2011

CAR

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Neurofibrillary tangles (NFTs) are one of the pathological hallmarks of Alzheimer’s disease (AD) and are primarily composed of aggregates of hyperphosphorylated forms of the microtubule associated protein tau. It is likely that an imbalance of kinase and phosphatase activities leads to the abnormal phosphorylation of tau and subsequent aggregation. The wide ranging therapeutic approaches that are being developed include to inhibit tau kinases, to enhance phosphatase activity, to promote microtubule stability, and to reduce tau aggregate formation and/or enhance their clearance with small molecule drugs or by immunotherapeutic means. Most of these promising approaches are still in preclinical development whilst some have progressed to Phase II clinical trials. By pursuing these lines of study, a viable therapy for AD and related tauopathies may be obtained.

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Section: Gsk3 Inhibitorsmentioning

confidence: 99%

“…It inhibits GSK3 mediated tau phosphorylation in cells by competing with ATP binding and it inhibits CDK2 as well (69). …”

Section: Gsk3 Inhibitorsmentioning

confidence: 99%

Tau as a Therapeutic Target for Alzheimers Disease

Boutajangout¹,

Sigurdsson²,

Krishnamurthy³

2011

CAR

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“…Paullones , a family of benzazepinones, includes the ATP competitive inhibitor alsterpaullone. The efficacy of alsterpaullone is 10-fold higher for GSK-3 than most cdks [52] and its administration reduces endogenous tau phosphorylation at putative GSK3 sites in the hippocampus of postnatal rats [50]. This compound also effectively and dose-dependently reduces tau toxicity in human tau-expressing drosophila [53].…”

Section: Tau-based Therapeutic Strategiesmentioning

confidence: 99%

“…This compound also effectively and dose-dependently reduces tau toxicity in human tau-expressing drosophila [53]. The structure of alsterpaullone suggests it is likely to be BBB permeable and have good tissue retention [52].…”

Section: Tau-based Therapeutic Strategiesmentioning

confidence: 99%

“…Maleimides of two major classes, bis-arylmaleimides and anilino-arylmaleimides, have been reported to be potent GSK-3 inhibitors. Of the bis-arylmaleimides, SB-216763, and SB-415286 (GlaxoSmithKline) show high selectivity for GSK3 against a panel of kinases [52]. SB-216763 reduces tau phosphorylation in postnatal rats [50], and reverses Aβ-induced tau phosphorylation, caspase-3 activation and nuclear DNA fragmentation [57].…”

Section: Tau-based Therapeutic Strategiesmentioning

confidence: 99%

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Advances in tau-based drug discovery

Noble

Pooler²,

Hanger³

2011

Expert Opinion on Drug Discovery

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Introduction-Tauopathies, including Alzheimer's disease (AD) and some frontotemporal dementias, are neurodegenerative diseases characterised by pathological lesions comprised of tau protein. There is currently a significant and urgent unmet need for disease-modifying therapies for these conditions and recently attention has turned to tau as a potential target for intervention.Areas covered-Increasing evidence has highlighted pathways associated with tau-mediated neurodegeneration as important targets for drug development. Here, the authors review recently published papers in this area and summarise the genetic and pharmacological approaches that have shown efficacy in reducing tau-associated neurodegeneration. These include the use of agents to prevent abnormal tau processing and increase tau clearance, therapies targeting the immune system, and the manipulation of tau pre-mRNA to modify tau isoform expression.Expert opinion-Several small molecule tau-based treatments are currently being assessed in clinical trials, the outcomes of which are eagerly awaited. Current evidence suggests that therapies targeting tau are likely, at least in part, to form the basis of an effective and safe treatment for Alzheimer's disease and related neurodegenerative disorders in which tau deposition is evident.

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Prediction of the binding mode between GSK3β and a peptide derived from GSKIP using molecular dynamics simulation

Tang

Chuang

et al. 2011

Biopolymers

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GSK3β plays an important role in many physiological functions; dysregulated GSK3β is involved in human diseases such as diabetes, cancer, and Alzheimer's disease. This study uses MD simulations to determine the interaction between GSK3β and a peptide derived from GSKIP, a novel GSK3β interacting protein. Results show that GSKIPtide is inlaid in a binding pocket consisting of an α-helix and an extended loop near the carboxy-terminal end. This binding pocket is hydrophobic, and is responsible for the protein-protein interaction of two other GSK3β interacting proteins: FRAT and Axin. The GSKIPtide binding mode is closer to that of AxinGID (in the Axin-GSK3-interacting domain). The single-point mutations of V267G and Y288F in GSK3β differentiate the binding modes between GSK3 and GSKIPtide, AxinGID, and FRATide. The V2677G mutation of GSK3β reduces the GSKIPtide binding affinity by 70% and abolishes the binding affinity with AxinGID, but has no effect on FRATide. However, GSK3β Y288F completely abolishes the FRATide binding without affecting GSKIPtide or AxinGID binding. An analysis of the GSK3β-GSKIPtide complex structure and the X-ray crystal structures of GSK3β-FRATide and GSK3β-AxinGID complexes suggests that the hydroxyl group of Y288 is crucial to maintaining a hydrogen bond network in GSK3β-FRATide. The hydrophobic side chain of V267 maintains the integrity of helix-helix ridge-groove hydrophobic interaction for GSK3β-GSKIPtide and GSK3β-AxinGID. This study simulates these two mutant systems to provide atomic-level evidence of the aforementioned experimental results and validate the wild-type complex structure prediction.

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GSK-3 Inhibitors for the Treatment of Alzheimer's Disease

Cited by 7 publications

References 96 publications

Tau as a Therapeutic Target for Alzheimers Disease

Tau as a Therapeutic Target for Alzheimers Disease

Advances in tau-based drug discovery

Prediction of the binding mode between GSK3β and a peptide derived from GSKIP using molecular dynamics simulation

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