AK-1

AK-1 is a sirtuin 2 (SIRT2) inhibitor (IC₅₀ = 12.5 µM).¹ It induces the formation of α-synuclein aggregates in H4 neuroglioma cells expressing α-synuclein and synphilin-1.² AK-1 (5 µM) decreases total cholesterol levels in Neuro2a and primary rat striatal neurons, as well as in hippocampal slice cultures.¹ It increases ubiquitination of hypoxia-inducible factor-1α (HIF-1α) in A549 cells and decreases HIF-1α levels in A549, HeLa, HEK293, and HEK293T cells under hypoxic conditions when used at a concentration of 10 µM.³ AK-1 (1 and 10 µM in the diet) decreases the loss of rhabdomeres in the ommatidium in the UAS-Httex1p-Q93 transgenic Drosophila model of Huntington's disease.⁴ Dietary administration of AK-1 (500 and 1,000 µM) prevents dopaminergic neuronal cell death in the dorsomedial cluster in the elav-GAL4 transgenic Drosophila model of Parkinson's disease.²

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1. 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).

2. Outeiro, T.F., Kontopoulos, E., Altmann, S.M., et al. Sirtuin 2 inhibitors rescue α-synuclein-mediated toxicity in models of Parkinson’s disease. Science 317(5837), 516-519 (2007).

3. Lee, S.D., Kim, W., Jeong, J.-W., et al. AK-1, a SIRT2 inhibitor, destabilizes HIF-1α and diminishes its transcriptional activity during hypoxia. Cancer Lett. 373(1), 138-145 (2016).

4. Luthi-Carter, R., Taylor, D.M., Pallos, J., et al. SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proc. Natl. Acad. Sci. USA 107(17), 7927-7932 (2010).