Tetrahydroquinoline-Capped Histone Deacetylase 6 Inhibitor SW-101 Ameliorates Pathological Phenotypes in a Charcot–Marie–Tooth Type 2A Mouse Model

Histone
deacetylase 6 (HDAC6) is a promising therapeutic target
for the treatment of neurodegenerative disorders. SW-100 (1a), a phenylhydroxamate-based HDAC6 inhibitor (HDAC6i) bearing a tetrahydroquinoline
(THQ) capping group, is a highly potent and selective HDAC6i that
was shown to be effective in mouse models of Fragile X syndrome and
Charcot–Marie–Tooth disease type 2A (CMT2A). In this
study, we report the discovery of a new THQ-capped HDAC6i, termed
SW-101 (1s), that possesses excellent HDAC6 potency and
selectivity, together with markedly improved metabolic stability and
druglike properties compared to SW-100 (1a). X-ray crystallography
data reveal the molecular basis of HDAC6 inhibition by SW-101 (1s). Importantly, we demonstrate that SW-101 (1s) treatment elevates the impaired level of acetylated α-tubulin
in the distal sciatic nerve, counteracts progressive motor dysfunction,
and ameliorates neuropathic symptoms in a CMT2A mouse model bearing
mutant MFN2. Taken together, these results bode well
for the further development of SW-101 (1s) as a disease-modifying
HDAC6i.