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Identification of a small molecule that selectively inhibits alpha-synuclein translational expression

Publication TypeJournal Article
Year of Publication2012
AuthorsRoss, NT, Metkar, SR, Le, H, Burbank, J, Cahill, C, Germain, A, Macpherson, L, Bittker, J, Palmer, M, Rogers, J, Schreiber, SL
Date Published2012/01/09

Alpha-synuclein is a protein implicated in the pathogenesis of neurodegenerative alpha-synucleinopathies including Parkinson’s disease (PD), the most prevalent movement disorder in humans. Evidence suggests that misregulation of alpha-synuclein translation plays a clear role in the pathology of this disease. Consequently, our therapeutic strategy is to limit alpha-synuclein translation. We report the outcome of a high-throughput chemical library screen to identify novel, nontoxic, and selective small-molecule inhibitors of alpha-synuclein expression, which will aid the development of therapies for PD and other neurodegenerative diseases. Of the 303,224-screened compounds, 36 hits were identified as inhibitors of alpha-synuclein expression and subsequently validated to confirm their inhibitory activity and selectivity. One of these compounds (ML150) displayed greater than 200-fold selective inhibition of alpha-synuclein expression compared with a related system and is inactive in a control system at the highest tested dose. Our results indicate that ML150 has a drug-like structure with no obvious chemical liabilities, excellent solubility, and stability in aqueous conditions. This new probe should be very useful in future cell-based investigations and in vivo studies of alpha-synuclein expression inhibition.