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


Journal Article

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.

Full Text

Cited Authors

  • Leyva, MJ; Degiacomo, F; Kaltenbach, LS; Holcomb, J; Zhang, N; Gafni, J; Park, H; Lo, DC; Salvesen, GS; Ellerby, LM; Ellman, JA

Published Date

  • November 2010

Published In

Volume / Issue

  • 17 / 11

Start / End Page

  • 1189 - 1200

PubMed ID

  • 21095569

Pubmed Central ID

  • 21095569

Electronic International Standard Serial Number (EISSN)

  • 1879-1301

International Standard Serial Number (ISSN)

  • 1074-5521

Digital Object Identifier (DOI)

  • 10.1016/j.chembiol.2010.08.014


  • eng