Identification and evaluation of small molecule pan-caspase inhibitors in Huntington's disease models

Chem Biol. 2010 Nov 24;17(11):1189-200. doi: 10.1016/j.chembiol.2010.08.014.

Abstract

Huntington's Disease (HD) is characterized by a mutation in the huntingtin (Htt) gene encoding an expansion of glutamine repeats on the N terminus of the Htt protein. Numerous studies have identified Htt proteolysis as a critical pathological event in HD postmortem human tissue and mouse HD models, and proteases known as caspases have emerged as attractive HD therapeutic targets. We report the use of the substrate activity screening method against caspase-3 and -6 to identify three novel, pan-caspase inhibitors that block proteolysis of Htt at caspase-3 and -6 cleavage sites. In HD models these irreversible inhibitors suppressed Hdh(111Q/111Q)-mediated toxicity and rescued rat striatal and cortical neurons from cell death. In this study, the identified nonpeptidic caspase inhibitors were used to confirm the role of caspase-mediated Htt proteolysis in HD. These results further implicate caspases as promising targets for HD therapeutic development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Caspase 3 / metabolism
  • Caspase 6 / metabolism
  • Caspase Inhibitors*
  • Cells, Cultured
  • Coumarins / chemistry
  • Coumarins / therapeutic use
  • Cysteine Proteinase Inhibitors / chemical synthesis
  • Cysteine Proteinase Inhibitors / chemistry*
  • Cysteine Proteinase Inhibitors / therapeutic use
  • Disease Models, Animal
  • Humans
  • Huntingtin Protein
  • Huntington Disease / drug therapy*
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / cytology
  • Neurons / drug effects
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Rats
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / therapeutic use
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • Caspase Inhibitors
  • Coumarins
  • Cysteine Proteinase Inhibitors
  • Htt protein, rat
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Small Molecule Libraries
  • Caspase 3
  • Caspase 6
  • 7-amino-4-methylcoumarin-3-acetic acid