Selective inhibitors of death in mutant huntingtin cells.
Huntington disease (HD) is an inherited neurodegenerative disorder with unclear pathophysiology. We developed a high-throughput assay in a neuronal cell culture model of HD, screened 43,685 compounds and identified 29 novel selective inhibitors of cell death in mutant huntingtin-expressing cells. Four compounds were active in diverse HD models, which suggests a role for cell death in HD; these compounds are mechanistic probes and potential drug leads for HD.
Varma
Hemant
H
Department of Biological Sciences, Columbia University, Fairchild Center, MC 2406, 1212 Amsterdam Avenue, New York, New York 10027, USA.
Voisine
Cindy
C
DeMarco
C Todd
CT
Cattaneo
Elena
E
Lo
Donald C
DC
Hart
Anne C
AC
Stockwell
Brent R
BR
D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics; D015394:Molecular Structure; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics*; D009930:Organic Chemicals / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D013329:Structure-Activity Relationship; D014162:Transfection
D061945:Caspase Inhibitors; D016895:Culture Media, Serum-Free; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D009930:Organic Chemicals; D053148:Caspase 3