IMR Press / FBE / Volume 4 / Issue 8 / DOI: 10.2741/E584

Frontiers in Bioscience-Elite (FBE) is published by IMR Press from Volume 13 Issue 2 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on as a courtesy and upon agreement with Frontiers in Bioscience.


A high-throughput screen to identify inhibitors of SOD1 transcription

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1 Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, United States
2 Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Harvard Medical School and Brigham and Women’s Hospital, Cambridge, MA 02139, United States
3 Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, United States
4 Neurological Surgery, Neurology, and Neurobiology Departments, University School of Medicine of Pittsburgh, Pittsburgh, PA 15213, United States
5 Geriatric Research Educational and Clinical Center (00-GR-H), V.A. Pittsburgh Healthcare System, 7180 Highland Drive, Pittsburgh, PA 15206, United States
6 Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
7 MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA 02129, United States

*Author to whom correspondence should be addressed.

Front. Biosci. (Elite Ed) 2012, 4(8), 2701–2708;
Published: 1 June 2012

Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disease. Approximately 20% 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 >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.

Amyotrophic lateral sclerosis
Cell based assays
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