Progress towards effective treatments for amyotrophic lateral sclerosis (ALS) has been hampered by the genetic heterogeneity of the disease and the difficulty of modeling progressive motor neuron pathology in a system amenable to rapid drug screening. This proposal takes advantage of recent discoveries of factors leading to ALS to develop a robust in vitro model that recapitulates ALS specific motor neuron degeneration. Use of this system for high-throughput screening has identified small molecules that rescue ALS motor neurons from cell death. The investigation of cellular mechanisms targeted by these small molecules (i.e., endoplasmic reticulum stress) has identified pathways that reverse disease processes and has identified novel routes for intervention and that will allow for identification of broadly relevant therapeutics. We have successfully identified a potent rescuer of ALS model motor neurons that has the potential to be developed into a therapeutic agent for both familial and sporadic ALS patients. Furthermore, we have identified the molecular target of this compound whose inhibition leads to reversal of the disease process. This proposal aims to optimize this compound's chemical and biological properties using a drug-discovery process involving computer-aided drug design, chemical synthesis, and in vitro and in vivo biological testing to produce a compound that is effective in animal models of ALS and suitable for evaluation in human clinical trials of ALS.