Tanespimycin: the opportunities and challenges of targeting heat shock protein 90
Tanespimycin: the opportunities and challenges of targeting heat shock protein 90
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DOI：
10.1517/13543780902953699
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发表时间：
2009-06-01
影响因子：
6.1
通讯作者：
Erlichman, Charles
中科院分区：
文献类型：
--
作者：
Erlichman, Charles
背景：热休克蛋白90(HSP90)是多伴侣复合体的核心，对许多参与肿瘤细胞增殖、存活和血管生成的客户蛋白的折叠、运输和稳定至关重要。靶向HSP90会导致这些客户蛋白的降解。目的：综述以热休克蛋白90为靶点的丹尼司匹霉素的研究进展。方法：介绍可用于坦尼司匹霉素开发的临床数据。结果：Tanespimycin生物活性剂量给药安全，不良反应轻微，如恶心、呕吐、腹泻、乏力。尽管单药研究显示活性有限，但丹尼斯皮霉素与波替佐米或曲妥珠单抗的联合应用分别为多发性骨髓瘤和乳腺癌的进一步评估提供了有前景的途径。结论：HSP90靶向策略的进一步发展包括测试具有更好的溶解性和稳定性的新的化学结构以及口服给药的可能性。靶向HSP90结合其他热休克蛋白，如HSP70或HSP27，可能是一种值得进一步探索的替代策略。
Background: Heat shock protein 90 (HSP90) is the core of a multi-chaperone complex critical for the folding, trafficking, and stabilization of many client proteins that are involved in tumor cell proliferation, survival, and angiogenesis. Targeting HSP90 results in degradation of these client proteins. Objective: Data supporting the development of tanespimycin, which targets HSP90, are reviewed. Methods: Clinical data available for tanespimycin development are presented. Results: Tanespimycin can be given safely at biologically active doses with mild toxicity such as nausea, vomiting, diarrhea, and fatigue. Although single-agent studies have shown limited activity, combinations of tanespimycin with bortezomib or trastuzumab have suggested promising avenues of further evaluation in multiple myeloma and breast cancer, respectively. Conclusions: Further development of HSP90-targeted strategies include testing of novel chemical structures having better solubility and stability and the potential for oral administration. Targeting of HSP90 in combination with other heat shock proteins, such as HSP70 or HSP27, may be an alternative strategy that warrants further exploration.