ArticleNeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics2024
Development of small-molecule Tau-SH3 interaction inhibitors that prevent amyloid-β toxicity and network hyperexcitability.
Article in Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 10 citations in OpenAlex.
- Fyn kinase: a key mechanistic regulator and therapeutic target in tauopathy and neurodegenerative diseases.Translational neurodegeneration · 2026Review
- Current review on inducible nitric oxide synthase and Src tyrosine kinase inhibitors as disease-modifiers in preclinical models of epilepsy.Histology and histopathology · 2026Review
- Identification and validation of efferocytosis-related biomarkers for the diagnosis of atherosclerosis based on bioinformatics and machine learning.European journal of medical research · 2025Article
- Multiple and Alternative Sites Make Tau Protein an Adaptable Sticky Surface for the SH3 Domain of Fyn Kinase.Angewandte Chemie (International ed. in English) · 2025Article
- Evidence that cholinergic mechanisms contribute to hyperexcitability at early stages in Alzheimer's disease.Frontiers in dementia · 2025Review
- Fyn Kinase in Alzheimer's Disease: Unraveling Molecular Mechanisms and Therapeutic Implications.Molecular neurobiology · 2025Review
- Conventional and Emerging Drug Targeting Sites in Alzheimer's Disease and the Role of Translational Informatics in its Diagnosis and Management.Current neuropharmacology · 2025Review
- Genetic forms of tauopathies: inherited causes and implications of Alzheimer's disease-like TAU pathology in primary and secondary tauopathies.Journal of neurology · 2024Review
- Disentangling tau: One protein, many therapeutic approaches.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Review
- Fyn, an important molecule in the brain, is a potential therapeutic target for brain tumours.Frontiers in pharmacology · 2024Review
- Enhanced Fyn-tau and NR2B-PSD95 interactions in epileptic foci in experimental models and human epilepsy.Brain communications · 2024Article
Corrections and comments
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Authors and funding
18 authors at 2 institutions in 1 country.
Funding
Abstract
Alzheimer's disease (AD) is the leading cause of dementia and lacks highly effective treatments. Tau-based therapies hold promise. Tau reduction prevents amyloid-β-induced dysfunction in preclinical models of AD and also prevents amyloid-β-independent dysfunction in diverse disease models, especially those with network hyperexcitability, suggesting that strategies exploiting the mechanisms underlying Tau reduction may extend beyond AD. Tau binds several SH3 domain-containing proteins implicated in AD via its central proline-rich domain. We previously used a peptide inhibitor to demonstrate that blocking Tau interactions with SH3 domain-containing proteins ameliorates amyloid-β-induced dysfunction. Here, we identify a top hit from high-throughput screening for small molecules that inhibit Tau-FynSH3 interactions and describe its optimization with medicinal chemistry. The resulting lead compound is a potent cell-permeable Tau-SH3 interaction inhibitor that binds Tau and prevents amyloid-β-induced dysfunction, including network hyperexcitability. These data support the potential of using small molecule Tau-SH3 interaction inhibitors as a novel therapeutic approach to AD.
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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.