Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A.
Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A.
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DOI：
10.1021/ja102758v
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发表时间：
2010-08-11
影响因子：
15
通讯作者：
Kozikowski, Alan P.
中科院分区：
文献类型：
--
作者：
Butler, Kyle V.;Kalin, Jay;Brochier, Camille;Vistoli, Guilio;Langley, Brett;Kozikowski, Alan P.
基于结构的药物设计结合同源性建模技术被用于开发有效的HDAC 6抑制剂，与其他抑制剂相比，其对HDAC 6同工酶显示出上级选择性。这些抑制剂可以在几个合成步骤中组装，因此易于放大用于体内研究。在原代皮层神经元培养物中测试了来自该系列的优化化合物，命名为Tubastatin A，其中发现其诱导乙酰化α-微管蛋白水平升高，但不诱导组蛋白，这与其HDAC 6选择性一致。Tubastatin A还在原代皮层神经元培养物中对谷胱甘肽耗竭诱导的氧化应激具有剂量依赖性保护作用。重要的是，当在所有测试浓度下单独给药时，这种含有异羟肟酸盐的HDAC 6选择性化合物没有显示出神经元毒性，因此预测了这种药剂及其类似物在神经退行性疾病中的潜在应用。
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.
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