Chiosis Gabriela, Lucas Brian, Huezo Henri, Solit David, Basso Andrea, Rosen Neal
Department of Medicine and Cell Biology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021, USA.
Curr Cancer Drug Targets. 2003 Oct;3(5):371-6. doi: 10.2174/1568009033481778.
The Hsp90 chaperones play a key role in regulating the physiology of cells exposed to environmental stress and in maintaining the malignant phenotype in tumor cells. Agents that interfere with the function of the chaperone may thus be beneficial in the treatment of cancers. The ansamycins (geldanamycin and herbimycin) and the unrelated natural product radicicol were found to bind to the N-terminal pocket of Hsp90 and inhibit its function. However, translation of these compounds to the clinic was impeded by stability and hepatoxicity issues. 17AAG, a derivative of geldanamycin, was found to be less hepatotoxic and is currently undergoing Phase I clinical trial. Unfortunately, 17AAG is insoluble, difficult to formulate and it is not yet clear if therapeutically effective doses can be administered without escalating non-Hsp90 associated toxicities. Additionally, for reasons not yet completely understood, a subset of tumor cells are insensitive to the action of the drug. The development of novel agents that lack the drawbacks of the natural products is thus necessary. Here we present an overview of such efforts with focus on a new class of purine-scaffold Hsp90 inhibitors developed by rational design.
热休克蛋白90（Hsp90）伴侣蛋白在调节暴露于环境应激的细胞生理以及维持肿瘤细胞的恶性表型方面发挥着关键作用。因此，干扰该伴侣蛋白功能的药物可能对癌症治疗有益。人们发现安莎霉素（格尔德霉素和赫司他汀）以及不相关的天然产物雷帕霉素能与Hsp90的N端口袋结合并抑制其功能。然而，这些化合物在临床应用中受到稳定性和肝毒性问题的阻碍。格尔德霉素的衍生物17-烯丙基氨基-17-去甲氧基格尔德霉素（17AAG）被发现肝毒性较小，目前正在进行I期临床试验。不幸的是，17AAG不溶，难以制成制剂，而且尚不清楚在不增加与非Hsp90相关毒性的情况下是否能够给予治疗有效剂量。此外，由于尚未完全理解的原因，一部分肿瘤细胞对该药物的作用不敏感。因此，开发没有天然产物缺点的新型药物是必要的。在此，我们概述了这方面的努力，重点介绍了通过合理设计开发的一类新型嘌呤骨架Hsp90抑制剂。
