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

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 alpha-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.…