A novel orally active HDAC6 inhibitor T-518 shows a therapeutic potential for Alzheimer's disease and tauopathy in mice.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Alzheimer Disease/*drug therapy ; Alzheimer Disease/*metabolism ; Histone Deacetylase 6/*antagonists & inhibitors ; Histone Deacetylase 6/*metabolism ; Histone Deacetylase Inhibitors/*administration & dosage ; Signal Transduction/*drug effects; Acetylation ; Administration, Oral ; Animals ; Axonal Transport/drug effects ; Axons/drug effects ; Axons/metabolism ; Cells, Cultured ; Cerebral Cortex/metabolism ; Disease Models, Animal ; Histone Deacetylase 6/genetics ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microtubules/metabolism ; Neurons/drug effects ; Neurons/metabolism ; Signal Transduction/genetics

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.
(© 2021. The Author(s).)

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0 (Histone Deacetylase Inhibitors)
EC 3.5.1.98 (HDAC6 protein, human)
EC 3.5.1.98 (Hdac6 protein, mouse)
EC 3.5.1.98 (Histone Deacetylase 6)

Date Created: 20210730 Date Completed: 20211108 Latest Revision: 20211108

20231215

PMC8322070

10.1038/s41598-021-94923-w

34326423