Protein Aggregation Inhibitors for ALS Therapy
Abstract
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 Cu/Zn 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 mg/kg bid), respectively. Maximum tolerated doses of all were high, indicating low toxicity. Four approaches were taken to identify protein target(s) 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2013
- Accession Number
- ADA585745
Entities
People
- Betty Diamond
- Donald R. Kirsch
- Richard Bruce Silverman
- Richard I. Morimoto
- Robert J. Ferrante
Organizations
- Northwestern University