Seo Young Ho
College of Pharmacy, Keimyung University, Daegu, Korea.
J Cancer Prev. 2015 Mar;20(1):5-11. doi: 10.15430/JCP.2015.20.1.5.
Heat shock protein 90 (Hsp90) is an adenosine triphosphate dependent molecular chaperone in eukaryotic cells that regulates the activation and maintenance of numerous regulatory and signaling proteins including epidermal growth factor receptor, human epidermal growth factor receptor 2, mesenchymal-epithelial transition factor, cyclin-dependent kinase-4, protein kinase B, hypoxia-inducible factor 1α, and matrix metalloproteinase-2. Since many of Hsp90 clients are oncogenic proteins, Hsp90 has become an attractive therapeutic target for treatment of cancer. To discover small molecule inhibitors targeting Hsp90 chaperone machinery, several strategies have been employed, which results in three classes of inhibitors such as N-terminal inhibitors, C-terminal inhibitors, and inhibitors disrupting protein-protein interactions of Hsp90 chaperone machinery. Developing small molecule inhibitors that modulate protein-protein interactions of Hsp90 is a challenging task, although it offers many alternative opportunities for therapeutic intervention. The lack of well-defined binding pocket and starting points for drug design challenges medicinal chemists to discover small molecule inhibitors disrupting protein-protein interactions of Hsp90. The present review will focus on the current studies on small molecule inhibitors disrupting protein-protein interactions of Hsp90 chaperone machinery, provide biological background on the structure, function and mechanism of Hsp90's protein-protein interactions, and discuss the challenges and promise of its small molecule modulations.
热休克蛋白90（Hsp90）是真核细胞中一种依赖三磷酸腺苷的分子伴侣，它调节多种调节蛋白和信号蛋白的激活与维持，这些蛋白包括表皮生长因子受体、人表皮生长因子受体2、间充质上皮转化因子、细胞周期蛋白依赖性激酶4、蛋白激酶B、缺氧诱导因子1α和基质金属蛋白酶-2。由于Hsp90的许多客户蛋白都是致癌蛋白，Hsp90已成为癌症治疗中一个有吸引力的治疗靶点。为了发现靶向Hsp90伴侣机制的小分子抑制剂，人们采用了多种策略，从而产生了三类抑制剂，如N端抑制剂、C端抑制剂以及破坏Hsp90伴侣机制蛋白-蛋白相互作用的抑制剂。尽管开发调节Hsp90蛋白-蛋白相互作用的小分子抑制剂为治疗干预提供了许多替代机会，但这仍是一项具有挑战性的任务。缺乏明确的结合口袋和药物设计起点，这对药物化学家发现破坏Hsp90蛋白-蛋白相互作用的小分子抑制剂构成了挑战。本综述将聚焦于目前关于破坏Hsp90伴侣机制蛋白-蛋白相互作用的小分子抑制剂的研究，提供Hsp90蛋白-蛋白相互作用的结构、功能和机制的生物学背景，并讨论其小分子调节的挑战与前景。
