Vertex Pharmaceuticals , 11010 Torreyana Road, San Diego, California 92121, United States.
J Med Chem. 2014 Apr 24;57(8):3382-400. doi: 10.1021/jm500042s. Epub 2014 Apr 10.
A structure-based drug design strategy was used to optimize a novel benzolactam series of HSP90α/β inhibitors to achieve >1000-fold selectivity versus the HSP90 endoplasmic reticulum and mitochondrial isoforms (GRP94 and TRAP1, respectively). Selective HSP90α/β 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 HSP90α/β selective inhibitors in treating chronic neurodegenerative indications such as Huntington's disease (HD). A potent, selective, orally available HSP90α/β inhibitor was identified (compound 31) that crosses the blood-brain barrier. Compound 31 demonstrated proof of concept by successfully reducing brain Htt levels following oral dosing in rats.
采用基于结构的药物设计策略，对新型苯并内酰胺 HSP90α/β 抑制剂系列进行优化，实现了对 HSP90 内质网和线粒体同工型（分别为 GRP94 和 TRAP1）的 >1000 倍选择性。研究发现，选择性 HSP90α/β 抑制剂在促进体外突变亨廷顿蛋白（mHtt）清除方面与 pan-HSP90 抑制剂等效，但细胞毒性更小。改善的耐受性特征可能使 HSP90α/β 选择性抑制剂能够用于治疗慢性神经退行性疾病，如亨廷顿病（HD）。鉴定出一种有效的、选择性的、口服可用的 HSP90α/β 抑制剂（化合物 31），该抑制剂能够穿过血脑屏障。化合物 31 通过在大鼠中口服给药成功降低脑 Htt 水平，证明了其概念验证。
