The sirtuin SIRT2 is a deacetylase which targets α-tubulin, histone 4, forkhead transcription factors, and several other substrates. It has roles in metabolic diseases, cancer, age-related disorders, and neurodegenerative diseases, potentially including Alzheimer’s, Huntington’s, and Parkinson’s diseases. AK-7 is a cell- and brain-permeable inhibitor of SIRT2 (IC50 = 15.5 μM). In culture, it diminishes neuronal cell death induced by mutant huntingtin fragment. In addition, AK-7 down-regulates cholesterol biosynthetic gene expression and reduces total cholesterol levels in neurons in vivo.
AK-7 is a deacetylase which targets α-tubulin, histone 4, forkhead transcription factors, and several other substrates it is also a selective SIRT2 inhibitor.
The brain-permeable small-molecule AK-7 inhibits the NAD-dependent deacetylase sirtuin 2 which is involved in cytoskeletal regulation and progression through mitosis. The inhibitor AK-7 specifically binds and inhibits SirT2 and has no apparent effect on SirT1 or SirT3. AK-7 reduced total cholesterol in primary striatal neurons and reduced cholesterol in cultured naïve neuronal cells and brain slices from wild-type mice. Treatment with AK-7 improved motor function, extended survival, and reduced brain atrophy in a pair of genetic mouse models of Huntington’s disease. In a study of aging in a rat model of Parkinson's disease, AK-7 inhibition revealed a potential role for SirT2 in Parkinson's neurodegeneration, and suggested that AK-7 may have a beneficial neuroprotective effect. Similar results were seen in a mouse model of Parkinson's disease, but AK-7 was not able to counteract neurodegenerative processes associated with amyotrophic lateral sclerosis or cerebral ischemia.
