Rational Design and Simple Chemistry Yield a Superior, Neuroprotective HDAC6 Inhibitor, Tubastatin A

By Kyle V. Butler, Jay H. Kalin, Camille Brochier, G. Vistoli, Brett C. Langley, A. Kozikowski. Journal of the American Chemical Society, 2010

730 citations recorded by the source corpus.

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, as 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 analogs to neurodegenerative conditions.

Subfields: Molecular Biology, Oncology, Pharmacology

View Paper: https://www.semanticscholar.org/paper/5fc0542f71e788eef76d1e405e7d2c2c14738530

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Citations in the corpus

• Foxp3 reprograms T cell metabolism to function in low glucose high lactate environments (2017, background): “The following references appear in the Supplemental Information: Butler et al. (2010); Endo et al. (1985).”