Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A

Kyle V. Butler, Jay Kalin, Camille Brochier, Guilio Vistoli, Brett Langley, Alan P. Kozikowski

Research output: Contribution to journalArticle

Abstract

Structure-based drug design combined with homology modeling techniques were used to develop potent inhibitors of HDAC6 that display superior selectivity for the HDAC6 isozyme compared to other inhibitors. These inhibitors can be assembled in a few synthetic steps, and thus are readily scaled up for in vivo studies. An optimized compound from this series, designated Tubastatin A, was tested in primary cortical neuron cultures in which it was found to induce elevated levels of acetylated α-tubulin, but not histone, consistent with its HDAC6 selectivity. Tubastatin A also conferred dose-dependent protection in primary cortical neuron cultures against glutathione depletion-induced oxidative stress. Importantly, when given alone at all concentrations tested, this hydroxamate-containing HDAC6-selective compound displayed no neuronal toxicity, thus, forecasting the potential application of this agent and its analogues to neurodegenerative conditions.

Original languageEnglish (US)
Pages (from-to)10842-10846
Number of pages5
JournalJournal of the American Chemical Society
Volume132
Issue number31
DOIs
StatePublished - Aug 11 2010

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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    Butler, K. V., Kalin, J., Brochier, C., Vistoli, G., Langley, B., & Kozikowski, A. P. (2010). Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A. Journal of the American Chemical Society, 132(31), 10842-10846. https://doi.org/10.1021/ja102758v