ACY-1083 is a brain-penetrant, highly selective histone deacetylase 6 (HDAC6) inhibitor (IC₅₀≈3nM). ACY-1083 inhibits HDAC6 to elevate α-tubulin acetylation, thereby improving microtubule/axonal transport and mitochondrial function. ACY-1083 is primarily used in mechanistic studies of HDAC6 function, chemotherapy-induced peripheral neuropathy (CIPN), and pharmacological research in nervous system injury-related models[1-4].
In vitro, during the oxygen-glucose deprivation/reoxygenation injury paradigm, ACY-1083 (30nM or 300nM) had been added to mouse hippocampal HT22 cells for 4h in the deprivation period. ACY-1083 had increased cell viability in a concentration-dependent manner, suppressed hypoxia-inducible factor-1α (HIF-1α) expression, and upregulated pro-survival signaling proteins such as phosphorylated mammalian target of rapamycin (p-mTOR) and heat shock protein 70 (HSP70)[5]. ACY-1083 (10μM) had been co-treated with TNF (5–50ng/ml) in human bronchial epithelial cells at the air-liquid interface for 8 days. ACY-1083 had reduced FITC-4kDa dextran paracellular permeability across the epithelium, and had attenuated TNF-stimulated secretion of IL-6, CCL2, and CXCL10[6].
In vivo, ACY-1083 (3mg/kg or 10mg/kg; once daily) had been intraperitoneally injected into adult male C57BL/6J mice with "stocking-glove" mechanical allodynia due to peripheral neuropathy for 7 or 14 consecutive days. ACY-1083 had effectively restored the mechanical withdrawal threshold in mice. ACY-1083 had elevated acetylated α-tubulin levels in the tibial nerve and improved mitochondrial oxygen consumption parameters (basal, ATP-coupled, proton leak, maximal respiration)[7]. ACY-1083 (10mg/kg/day; once daily) had been intraperitoneally injected into C57BL/6J mice in a doxorubicin-related cognitive impairment model for 14 consecutive days. ACY-1083 had significantly restored spatial/working memory and executive function in mice[8].
References:
[1] Vieson MD, Gojmerac AM, Khan D, et al. Treatment with a selective histone deacetylase 6 inhibitor decreases lupus nephritis in NZB/W mice. Histol Histopathol. 2017 Dec;32(12):1317-1332.
[2] Biesterveld BE, Wakam GK, Kemp MT, et al. Histone deacetylase 6 inhibition improves survival in a swine model of lethal hemorrhage, polytrauma, and bacteremia. J Trauma Acute Care Surg. 2020 Nov;89(5):932-939.
[3] Porter NJ, Mahendran A, Breslow R, et al. Unusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors. Proc Natl Acad Sci U S A. 2017 Dec 19;114(51):13459-13464.
[4] Martinez VK, McAlpin BR, Singh AK, et al. Single-Nucleus RNA Sequencing of HDAC6 Inhibition in Resolving Doxorubicin-Induced Cognitive Impairment. Mol Neurobiol. 2025 Oct;62(10):13557-13575.
[5] Nikolian VC, Dennahy IS, Weykamp M, et al. Isoform 6-selective histone deacetylase inhibition reduces lesion size and brain swelling following traumatic brain injury and hemorrhagic shock. J Trauma Acute Care Surg. 2019 Feb;86(2):232-239.
[6] Horndahl J, Svärd R, Berntsson P, et al. HDAC6 inhibitor ACY-1083 shows lung epithelial protective features in COPD. PLoS One. 2022 Oct 12;17(10):e0266310.
[7] Krukowski K, Ma J, Golonzhka O, et al. HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy. Pain. 2017 Jun;158(6):1126-1137.
[8] McAlpin BR, Mahalingam R, Singh AK, et al. HDAC6 inhibition reverses long-term doxorubicin-induced cognitive dysfunction by restoring microglia homeostasis and synaptic integrity. Theranostics. 2022 Jan 1;12(2):603-619.