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Review

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

Nathan T Ross  1 , Shailesh R Metkar  1 , Hanh Le  1 , Jason Burbank  1 , Catherine Cahill  2 , Andrew Germain  1 , Lawrence MacPherson  1 , Joshua Bittker  1 , Michelle Palmer  1 , Jack Rogers  2 , Stuart L Schreiber  1   3
In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010.
[updated ].
Affiliations
Review

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

Nathan T Ross et al.

Excerpt

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.

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