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Updated: May 21, 2026
Genetic Screen for Identification of Multicopy Suppressors in Schizosaccharomyces pombe
Published on: September 13, 2022
A high-throughput screen to identify inhibitors of SOD1 transcription
Paul D Wright1, Nicholas Wightman, Mickey Huang
1Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA. Paulwright27@ymail.com
Abstract:
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.
Insights
Researchers screened compounds to inhibit the gene expression of copper-zinc superoxide dismutase (SOD1), a cause of familial amyotrophic lateral sclerosis (ALS). While a compound showed some inhibitory effect, it is unlikely to be clinically useful for ALS treatment.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease.
- Mutations in the copper-zinc superoxide dismutase (SOD1) gene cause approximately 20% of familial ALS cases.
- SOD1 levels influence disease onset and progression in rodent models.
Purpose of the Study:
- To investigate if reducing SOD1 protein levels could be a therapeutic strategy for ALS.
- To screen for small molecules that inhibit SOD1 gene transcription.
Main Methods:
- A large-scale screening of 30,000 compounds was performed to identify SOD1 transcription inhibitors.
- The efficacy of the most potent inhibitor (Compound ID 7687685) was tested in cell lines (PC12, HeLa) and mouse spinal cord tissue.
Main Results:
- N-{4-[4-(4-methylbenzoyl)-1-piperazinyl]phenyl}-2-thiophenecarboxamide (Compound ID 7687685) was identified as an inhibitor of SOD1 transcription.
- Compound 7687685 showed an EC50 of 10.6 microM for SOD1 expression inhibition in PC12 cells and an LD50 >30 microM.
- The compound reduced endogenous SOD1 levels in HeLa cells and modestly reduced SOD1 protein in mouse spinal cord tissue.
Conclusions:
- Compound 7687685 demonstrated inhibition of SOD1 gene expression but is unlikely to be clinically useful for ALS treatment.
- The screening strategy employed could be broadly applicable for discovering small molecule inhibitors of gene expression.
