Abstract
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.
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Acknowledgements
We gratefully acknowledge the support of the High Q Foundation (H.V.), the Hereditary Disease Foundation (C.V. and B.R.S.), Cure Huntington Disease Initiative (B.R.S. and D.C.L.), Fondazione Telethon Onlus (E.C.) and the US National Institutes of Health (A.C.H.). B.R.S. is supported in part by a Career Award at the Scientific Interface from the Burroughs Wellcome Fund.
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H.V. and B.R.S. designed the screen and wrote the manuscript. E.C. provided essential reagents, cell lines and advice. H.V. performed the high-throughput screen and tested compounds in PC12 and yeast HD models. H.V., C.V. and A.C.H. designed the C. elegans assay; H.V. and C.V. performed the C. elegans assay. C.T.D. and D.C.L. designed the brain slice assay, C.T.D. tested compounds in the assay and D.C.L. performed analysis of the data.
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The authors declare no competing financial interests.
Supplementary information
Supplementary Fig. 1
Flow diagram of hit prioritization scheme. (PDF 72 kb)
Supplementary Fig. 2
Effect of hit compounds on N548 mutant htt transgene expression. (PDF 104 kb)
Supplementary Fig. 3
Efficacy of R1 to R4 in diverse HD models. (PDF 276 kb)
Supplementary Fig. 4
Caspase activation by SDM in ST14A HD model and effect of R2 and R3 on caspase-3/7 cleavage. (PDF 95 kb)
Supplementary Table 1
Structures of selective hits. (PDF 166 kb)
Supplementary Table 2
Novel compounds' activity in various HD models. (PDF 16 kb)
Supplementary Table 3
Medicinal chemistry profiles of novel compounds and structure-activity relationship for R1 and R4. (PDF 84 kb)
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Varma, H., Voisine, C., DeMarco, C. et al. Selective inhibitors of death in mutant huntingtin cells. Nat Chem Biol 3, 99–100 (2007). https://doi.org/10.1038/nchembio852
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DOI: https://doi.org/10.1038/nchembio852
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