ArticleScientific reports2021
A novel orally active HDAC6 inhibitor T-518 shows a therapeutic potential for Alzheimer's disease and tauopathy in mice.
Article in Scientific reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 2 of them syntheses that pooled it.
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Who cites it
33 citing papers in PubMed, 2 syntheses or guidelines pooled it, 52 citations in OpenAlex.
- Exploration of current situation of psychotropic drugs research and development in China based on drug clinical trials.Frontiers in psychiatry · 2025Pooled it
- Drug repurposing on Alzheimer's disease through modulation of NRF2 neighborhood.Redox biology · 2023Pooled it
- An integrated machine learning and chemical space network approach for the design of potent epigenetic HDAC6 inhibitors for targeting neurological disorders.Molecular diversity · 2026Article
- Pharmacological Inhibition of HDAC6 Transiently Reduces Voluntary Ethanol Consumption in Male Mice.Alcohol, clinical & experimental research · 2026Article
- Identification of a mechanism-based binding mode for a histone deacetylase 6 inhibitor.Nature communications · 2026Article
- A next-generation HDAC6 inhibitor for amyotrophic lateral sclerosis and frontotemporal dementia.Brain : a journal of neurology · 2026Article
- The neuroprotective effect of Cucurbitacin B against Aβ and tau toxicities requires functional HDAC6 and stress granule pathways.Biogerontology · 2026Article
- Recommended Tool Compounds: Isoform- and Class-Specific Histone Deacetylase Inhibitors.ACS pharmacology & translational science · 2026Review
- HDAC6 Inhibition Reduces Seeded Tau and α-Synuclein Pathologies in Primary Neuron Cultures and Wild-Type Mice.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Gut Microbiome-Sphingolipid Metabolism-Brain Axis Interactions: Neuroprotective Effects of Amitriptyline as Functional Inhibitor of Acid Sphingomyelinase in a Mouse Model of Tauopathy.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2026Article
- Discovery of Pyrazole-Based Positron Emission Tomography Agent that Maps Histone Deacetylase 6 (HDAC6) in the Nonhuman Primate Brain.Journal of medicinal chemistry · 2025Article
- Review
- Advancements in Hydrazide-Based HDAC Inhibitors: A Review of Recent Developments and Therapeutic Potential.Journal of medicinal chemistry · 2025Review
- Structure similarity based screening coupled to integrated structural biochemistry approach for exploring the high affinity inhibitors against histone deacetylase (HDAC)-6.In silico pharmacology · 2025Article
- Review
- Preclinical validation of a novel brain-penetrant PET ligand for visualization of histone deacetylase 6: a potential imaging target for neurodegenerative diseases.European journal of nuclear medicine and molecular imaging · 2024Article
- Step-by-step optimisation of the radiosynthesis of the brain HDAC6 radioligand [EJNMMI radiopharmacy and chemistry · 2024Article
- Mechanistic and Structural Insights on Difluoromethyl-1,3,4-oxadiazole Inhibitors of HDAC6.International journal of molecular sciences · 2024Article
- Chemical Versatility in Catalysis and Inhibition of the Class IIb Histone Deacetylases.Accounts of chemical research · 2024Review
- 2-(Difluoromethyl)-1,3,4-oxadiazoles: The Future of Selective Histone Deacetylase 6 Modulation?ACS pharmacology & translational science · 2024Article
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Accumulation of tau protein is a key pathology of age-related neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Those diseases are collectively termed tauopathies. Tau pathology is associated with axonal degeneration because tau binds to microtubules (MTs), a component of axon and regulates their stability. The acetylation state of MTs contributes to stability and histone deacetylase 6 (HDAC6) is a major regulator of MT acetylation status, suggesting that pharmacological HDAC6 inhibition could improve axonal function and may slow the progression of tauopathy. Here we characterize N-[(1R,2R)-2-{3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl}cyclohexyl]-2,2,3,3,3-pentafluoropropanamide (T-518), a novel, potent, highly selective HDAC6 inhibitor with clinically favorable pharmacodynamics. T-518 shows potent inhibitory activity against HDAC6 and superior selectivity over other HDACs compared with the known HDAC6 inhibitors in the enzyme and cellular assays. T-518 showed brain penetration in an oral dose and blocked HDAC6-dependent tubulin deacetylation at Lys40 in mouse hippocampus. A 2-week treatment restored impaired axonal transport and novel object recognition in the P301S tau Tg mouse, tauopathy model, while a 3-month treatment also decreased RIPA-insoluble tau accumulation. Pharmaceutical inhibition of HDAC6 is a potential therapeutic strategy for tauopathy, and T-518 is a particularly promising drug candidate.
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