|Publication Type||Journal Article|
|Year of Publication||2012|
|Authors||Ross, NT, Metkar, SR, Le, H, Burbank, J, Cahill, C, Germain, A, Macpherson, L, Bittker, J, Palmer, M, Rogers, J, Schreiber, SL|
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.