Abstract

HDAC6 Inhibition: Getting Microtubule Transport Back on Track

Matthew Jarpe, Associate Vice President Of Biology, Acetylon Pharmaceuticals

Histone deacetylase 6 is a cytoplasmic enzyme that removes acetyl modifications from lysines of tubulin. Acetylated tubulin is found in stabilized microtubules. Cargo transport occurs more efficiently along the stabilized microtubules and neurons are particularly sensitive to disruptions in microtubule transport. Peripheral neuropathies, both in motor and sensory nerves, as well as neurodegenerative diseases in the CNS, are characterized by a loss of fast axonal transport. Inhibition of HDAC6 has been found to restore fast axonal transport in neurons. HDAC6 inhibitors are effective in animal models of peripheral neuropathy and neurodegeneration. The effect of these compounds on disease symptoms persists following drug withdrawal, suggesting a disease modifying effect. Acetylon has developed highly selective HDAC6 inhibitors, both brain penetrant and non-penetrant, for the treatment of neuronal diseases. Activity of two HDAC6 inhibitors, the brain penetrant compound ACY-738 and the non-penetrant compound ACY-1215, in animal models of Alzheimer’s disease and peripheral neuropathy, will be presented.