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Novel therapeutics

Active state

Nature Reviews Cancer volume 3, page 804 (2003)Cite this article

Kamal and colleagues first showed that 17-AAG does have a higher affinity for HSP90 in tumour cells — in this case, BT474 breast carcinoma cells (IC50 6 nM) — than in normal cells (IC50 600 nM). 17-AAG specifically inhibits the ATP-binding site of HSP90, and the binding affinity of ATP was tenfold higher in the tumour cell lines. 17-AAG also had higher affinity for HSP90 in ERBB2-overexpressing cancer cell lines.

To understand how HSP90 differs between normal and tumour cells, the authors looked at the levels of two essential components of multichaperone HSP90 complexes — P23 and HOP — in the cell lines. They used immunoprecipitation assays to show that more HSP90 was present in complexes with P23 and HOP in tumour cells compared with normal cells. Tumour HSP90 also had markedly higher ATPase activity than HSP90 from normal cells.

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ORIGINAL RESEARCH PAPER

  1. Kamal, A. et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425, 407–410 (2003)

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  1. Ezzie Hutchinson
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Hutchinson, E. Active state. Nat Rev Cancer 3, 804 (2003). https://doi.org/10.1038/nrc1223

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