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.