A high-throughput screen to identify inhibitors of SOD1 transcription.

Paul D. Wright, Nicholas Wightman, Mickey Huang, Alexandra Weiss, Peter C. Sapp, Gregory D. Cuny, Adrian J. Ivinson, Marcie A. Glicksman, Robert J. Ferrante, Wayne Matson, Samantha Matson, Robert H. Brown

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disease. Approximately 20 percent of familial ALS cases are caused by mutations in the Cu/Zn superoxide dismutase (SOD1) gene. Rodents expressing mutant SOD1 transgenes develop progressive, fatal motor neuron disease and disease onset and progression is dependent on the level of SOD1. We investigated the possibility that a reduction in SOD1 protein may be of therapeutic benefit in ALS and screened 30,000 compounds for inhibition of SOD1 transcription. The most effective inhibitor identified was N-{4-[4-(4-methylbenzoyl)-1-piperazinyl]phenyl}-2-thiophenecarboxamide (Compound ID 7687685), which in PC12 cells showed an EC50 of 10.6 microM for inhibition of SOD1 expression and an LD50 more than 30 microM. This compound was subsequently shown to reduce endogenous SOD1 levels in HeLa cells and to exhibit a modest reduction of SOD1 protein levels in mouse spinal cord tissue. These data suggest that the efficacy of compound 7687685 as an inhibitor of SOD1 gene expression is not likely to be clinically useful, although the strategy reported could be applied broadly to screening for small molecule inhibitors of gene expression.

Original languageEnglish (US)
Pages (from-to)2801-2808
Number of pages8
JournalFrontiers in bioscience (Elite edition)
StatePublished - 2012
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine


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