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.
Highlights
Accumulation of tau protein is a key pathology of age-related neurodegenerative diseases such as Alzheimer’s disease and progressive supranuclear palsy
In addition to the screening assay, HDAC selectivity profile of T-518 was evaluated by HDAC panel and compared with other well-known hydroxamate histone deacetylase 6 (HDAC6) inhibitors such as ACY-738, Ricolinostat, and Tubastatin A (Figure S1)
These findings suggest that selectivity for other HDACs such as class I can alter H3 acetylation and T-518 is highly selective for HDAC6 both in both cell free system and mammalian neurons
Summary
Accumulation of tau protein is a key pathology of age-related neurodegenerative diseases such as Alzheimer’s disease and progressive supranuclear palsy In addition to AD, axonal damage is associated with the severity and progression of other neurodegenerative diseases such as frontotemporal degeneration[15,16] In these diseases, tau accumulation is commonly observed in the brain and they are collectively termed tauopathy. We report that the novel HDAC6 inhibitor T-518 harboring oxadiazole instead of hydroxamate as the ZBG acts as a potent, selective, orally bioavailable, and brain-penetrant HDAC6 inhibitor, and that T-518 has therapeutic effects in a mouse model of tauopathy
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