Sirtuin 2 (
SIRT2) deacetylase-dependent inhibition mediates neuroprotective reduction of
cholesterol biosynthesis in an in vitro
Huntington's disease model. This study sought to identify the first brain-permeable
SIRT2 inhibitor and to characterize its
cholesterol-reducing properties in neuronal models. Using biochemical
sirtuin deacetylation assays, we screened a brain-permeable in silico compound library, yielding
3-(1-azepanylsulfonyl)-N-(3-bromphenyl)benzamide as the most potent and selective
SIRT2 inhibitor. Pharmacokinetic studies demonstrated brain-permeability but limited metabolic stability of the selected candidate. In accordance with previous observations, this
SIRT2 inhibitor stimulated cytoplasmic retention of
sterol regulatory
element binding protein-2 and subsequent transcriptional downregulation of
cholesterol biosynthesis genes, resulting in reduced total
cholesterol in primary striatal neurons. Furthermore, the identified inhibitor reduced
cholesterol in cultured naïve neuronal cells and brain slices from wild-type mice. The outcome of this study provides a clear opportunity for lead optimization and
drug development, targeting metabolic dysfunctions in CNS disorders where abnormal
cholesterol homeostasis is implicated.