Discovery of 1,3,4-oxidiazole scaffold compounds as inhibitors of superoxide dismutase expression

Thomas J. Lukas*, Gary E. Schiltz, Hasan Arrat, Karl Scheidt, Teepu Siddique

*Corresponding author for this work

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

The treatment of neurodegenerative diseases is difficult because of multiple etiologies and the interplay of genetics and environment as precipitating factors. In the case of amyotrophic lateral sclerosis (ALS), we have knowledge of a handful of genes that cause disease when mutated. However, drugs to counteract the effect of genetic mutations have not yet been found. One of the causative genes, Cu, Zn-superoxide dismutase (SOD1) is responsible for about 10-15% of the genetically linked autosomal dominant disease. Our rationale was that compounds that reduce expression of the mutant protein would be beneficial to slow onset and/or disease progression. We screened candidate compounds using a cell-based in vitro assay for those that reduce mutant SOD1 (G93A) protein expression. This led to the discovery of 2-[3-iodophenyl) methylsulfanyl]-5pyridin-4-yl-1,3,4-oxadiazole, a known protein kinase inhibitor that decreases G93A-SOD1 expression in vitro and in the brain and spinal cord in vivo. However, this compound has a biphasic dose response curve and a likely toxophore which limit its therapeutic window for chronic disease such as ALS. Therefore, we designed and tested a focused library of analogs for their ability to decrease SOD1 expression in vitro. This exercise resulted in the identification of a lead compound with improved drug-like characteristics and activity. Development of small molecules that reduce the expression of etiologically relevant toxic proteins is a strategy that may also be extended to familial ALS linked to gain of function mutations in other genes.

Original languageEnglish (US)
Pages (from-to)1532-1537
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number6
DOIs
StatePublished - Mar 15 2014

Keywords

  • Amyotrophic lateral sclerosis
  • Chemical synthesis
  • Hit-to-lead
  • Inhibitor
  • Pharmacokinetics
  • Superoxide dismutase
  • Transgenic mouse

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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