AK-7

The sirtuin SIRT2 is a deacetylase which targets α-tubulin, histone 4, forkhead transcription factors, and several other substrates.¹ It has roles in metabolic diseases, cancer, age-related disorders, and neurodegenerative diseases, potentially including Alzheimer’s, Huntington’s, and Parkinson’s diseases.^1,2,3 AK-7 is a cell- and brain-permeable inhibitor of SIRT2 (IC₅₀ = 15.5 μM).⁴ In culture, it diminishes neuronal cell death induced by mutant huntingtin fragment.⁴ In addition, AK-7 down-regulates cholesterol biosynthetic gene expression and reduces total cholesterol levels in neurons in vivo.⁴

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1. de Oliveira, R.M., Sarkander, J., Kazantsev, A.G., et al. SIRT2 as a therapeutic target for age-related disorders. Front. Pharmacol. 3, 82 (2012).

2. Fridén-Saxin, M., Seifert, T., Landergren, M.R., et al. Synthesis and evaluation of substituted chroman-4-one and chromone derivatives as sirtuin 2-selective inhibitors. J. Med. Chem. 55(16), 7104-7113 (2012).

3. Xu, K., Dai, X.L., Huang, H.C., et al. Targeting HDACs: A promising therapy for Alzheimer’s disease. Oxid. Med. Cell. Longev. 143269 (2011).

4. Taylor, D.M., Balabadra, U., Xiang, Z., et al. A brain-permeable small molecule reduces neuronal cholesterol by inhibiting activity of sirtuin 2 deacetylase. ACS Chem Biol. 6(6), 540-546 (2011).