Tanespimycin: the opportunities and challenges of targeting heat shock protein 90.

摘要

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.