ACY-738

ACY-738 is an inhibitor of histone deacetylase 6 (HDAC6; IC₅₀ = 1.7 nM).¹ It is selective for HDAC6 over HDAC1-3 (IC₅₀s = 94, 128, and 218 nM, respectively). ACY-738 (5 mg/kg) increases acetylation of α-tubulin in mouse brain. It increases exploratory activity in a novel open-field test and reduces immobility time in a tail suspension test in wild-type, but not neural cell-selective HDAC6 knockout, mice when administered at a dose of 50 mg/kg, indicating anxiolytic and antidepressant-like activity, respectively. ACY-738 (100 mg/kg in the diet) attenuates decreases in caudal nerve sensory nerve action potential (SNAP) amplitude and increases in hind paw mechanical hypersensitivity in a mouse model of peripheral neuropathy induced by vincristine (Item No. 11764).² It decreases hepatorenal cystogenesis in a rat model of polycystic liver disease when administered at a dose of 30 mg/kg.³

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1. Jochems, J., Boulden, J., Lee, B.G., et al. Antidepressant-like properties of novel HDAC6-selective inhibitors with improved brain bioavailability. Neuropsychopharmacology 39(2), 389-400 (2014).

2. Van Helleputte, L., Kater, M., Cook, D.P., et al. Inhibition of histone deacetylase 6 (HDAC6) protects against vincristine-induced peripheral neuropathies and inhibits tumor growth. Neurobiol. Dis. 111, 59-69 (2018).

3. Lorenzo Pisarello, M., Masyuk, T.V., Gradilone, S.A., et al. The combination of an HDAC6 inhibitor and a somatostatin receptor agonist synergistically reduces hepato-renal cystogenesis in an animal model of polycystic liver disease. Am. J. Pathol. 188(4), 981-994 (2018).