title: Identification and evaluation of small molecule pan-caspase inhibitors in Huntington's disease models.
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.
authors.affiliation: Department of Chemistry, University of California, Berkeley, CA 94720, USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Leyva
authors.forename: Francesco
authors.initials: F
authors.lastname: Degiacomo
authors.forename: Linda S
authors.initials: LS
authors.lastname: Kaltenbach
authors.forename: Jennifer
authors.initials: J
authors.lastname: Holcomb
authors.forename: Ningzhe
authors.initials: N
authors.lastname: Zhang
authors.forename: Juliette
authors.initials: J
authors.lastname: Gafni
authors.forename: Hyunsun
authors.initials: H
authors.lastname: Park
authors.forename: Donald C
authors.initials: DC
authors.lastname: Lo
authors.forename: Guy S
authors.initials: GS
authors.lastname: Salvesen
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ellerby
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Ellman
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053178:Caspase 6 / Q000378:metabolism; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D003374:Coumarins / Q000737:chemistry / Q000627:therapeutic use; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D061945:Caspase Inhibitors; D003374:Coumarins; D015853:Cysteine Proteinase Inhibitors; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D054852:Small Molecule Libraries; D053148:Caspase 3; D053178:Caspase 6; C051029:7-amino-4-methylcoumarin-3-acetic acid