Protein Aggregation Inhibitors for ALS Therapy
Final rept. 1 Jul 2010-30 Jun 2013
NORTHWESTERN UNIV EVANSTON IL
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Amyotrophic lateral sclerosis ALS is a fatal neurodegenerative disease characterized by progressive loss of motor neurons, leading to death within 3-5 years. Gulf War veterans, and military personnel in general, exhibit a significant increased risk of developing ALS. There is no effective treatment for ALS riluzole, the only FDA-approved drug for ALS, extends median survival by only 2-3 months. The genetic linkage of several mutations in the gene for CuZn superoxide dismutase SOD 1 in some cases of familial ALS provided the first indication of a potential causal factor in the disease. We identified three chemotypes pyrazolones, cyclohexane-1,3-diones, and pyrimidine-2,4,6-triones that provide protection from toxicity and block aberrant protein aggregation caused by mutant SOD1. Each of these chemotypes was modified to improve potency and pharmacological properties our best compounds in each chemotype extended life of the ALS mouse model by 13, 13, and 31 10 mgkg bid, respectively. Maximum tolerated doses of all were high, indicating low toxicity. Four approaches were taken to identify protein targets of the pyrazole class. Affinity bait experiments identified proteins involved in proteasomal activation photoaffinity experiments identified heat shock protein HSP 27 and related proteins. All of these results provide new potential treatments for ALS.
- Medicine and Medical Research