Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are detected in 20% of 
familial and 3% of sporadic amyotrophic lateral sclerosis (ALS) cases. Although 
mutant SOD1 is known to induce motor neuron death via multiple adverse acquired 
functions, its exact pathogenic mechanism is not well defined. SOD1 toxicity is 
dose dependent; levels of mutant SOD1 protein in transgenic mice determine 
disease susceptibility, onset and rate of progression. We therefore sought to 
identify small molecules that reduce SOD1 levels by inhibiting the SOD1 
promoter. We tested pyrimethamine (previously reported to suppress SOD1 
expression), several compounds currently in trials in human and murine ALS, and 
a set of 1040 FDA-approved compounds. In a PC12 cell-based assay, no compounds 
reduced SOD1 promoter activity without concomitant cytotoxicity. Additionally, 
pyrimethamine failed to repress levels of SOD1 protein in HeLa cells or 
homogenates of liver, spinal cord and brain of wild-type mice. Thirty-four 
compounds (including riluzole, ceftriaxone, minocyclin, PBA, lithium, 
acetylcysteine) in human and mouse ALS trials and an additional set of 1040 
FDA-approved compounds also showed no effect on SOD1 promoter activity. This 
present study thus failed to identify small molecule inhibitors of SOD1 gene 
expression.