Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Curr Top Med Chem. 2009;9(15):1436-46. doi: 10.2174/156802609789895737.
Hsp90 is a molecular chaperone with important roles in regulating the function of several proteins with potential pathogenic activity. Because many of these proteins are involved in cancer and neurodegenerative promoting pathways, Hsp90 has emerged as an attractive therapeutic target in these diseases. Molecules that bind to the N-terminal nucleotide pocket of Hsp90 inhibit its activity, and consequently, disrupt client protein function. A number of these inhibitors from several chemical classes are now known, and some are already in clinical trials. This review focuses on the purine class of Hsp90 inhibitors, their discovery through rational design, and on efforts aimed towards their optimization and development into clinically viable drugs for the treatment of cancer. Their potential towards neurodegenerative diseases will also be touched upon.
Hsp90 是一种分子伴侣，在调节具有潜在致病活性的几种蛋白质的功能方面发挥着重要作用。由于这些蛋白质中的许多都参与了癌症和神经退行性疾病的促进途径，因此 Hsp90 已成为这些疾病中一个有吸引力的治疗靶点。与 Hsp90 的 N 端核苷酸口袋结合的分子抑制其活性，从而破坏客户蛋白的功能。目前已经发现了来自几个化学类别的许多此类抑制剂，其中一些已经在临床试验中。这篇综述主要关注 Hsp90 抑制剂的嘌呤类，通过合理设计的发现，以及努力优化和开发它们成为治疗癌症的临床可行药物。它们在神经退行性疾病方面的潜力也将涉及。
