Identification of Novel HSP90伪/尾 Isoform Selective Inhibitors Using Structure-Based Drug Design. Demonstration of Potential Utility in Treating CNS Disorders such as Huntington鈥檚 Disease

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• 作者：Justin T. Ernst ; Timothy Neubert ; Michael Liu ; Samuel Sperry ; Harmon Zuccola ; Amy Turnbull ; Beth Fleck ; William Kargo ; Lisa Woody ; Peggy Chiang ; Dao Tran ; Weichao Chen ; Phillip Snyder ; Timothy Alcacio ; Azin Nezami ; James Reynolds ; Khisal Alvi ; Lance Goulet ; Dean Stamos
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：April 24, 2014
• 年：2014
• 卷：57
• 期：8
• 页码：3382-3400
• 全文大小：894K
• 年卷期：v.57,no.8(April 24, 2014)
• ISSN：1520-4804

文摘

A structure-based drug design strategy was used to optimize a novel benzolactam series of HSP90伪/尾 inhibitors to achieve >1000-fold selectivity versus the HSP90 endoplasmic reticulum and mitochondrial isoforms (GRP94 and TRAP1, respectively). Selective HSP90伪/尾 inhibitors were found to be equipotent to pan-HSP90 inhibitors in promoting the clearance of mutant huntingtin protein (mHtt) in vitro, however with less cellular toxicity. Improved tolerability profiles may enable the use of HSP90伪/尾 selective inhibitors in treating chronic neurodegenerative indications such as Huntington鈥檚 disease (HD). A potent, selective, orally available HSP90伪/尾 inhibitor was identified (compound 31) that crosses the blood鈥揵rain barrier. Compound 31 demonstrated proof of concept by successfully reducing brain Htt levels following oral dosing in rats.