Heat-shock protein 90 inhibitors as novel cancer chemotherapeutics - an update.

Heat-shock protein 90 (Hsp90) is a molecular chaperone whose association is required for stability and function of a growing number of signalling proteins that have been implicated in cancer cell survival, including several mutated proteins that are only found in specific cancers. Furthermore, a growing body of evidence suggests that cancer cells are particularly dependent on Hsp90 for their growth and survival, and, therefore, are more sensitive to the effects of its inhibition than are non-transformed cells and tissues. Several chemically distinct Hsp90 inhibitors have shown encouraging antitumour activity in multiple preclinical model systems, and one Hsp90 inhibitor, the benzoquinone ansamycin 17-allylamino, 17-demethoxygeldanamycin, has completed five Phase I clinical trials, with a number of Phase II trials soon to be underway or in progress. Other Hsp90 inhibitors are either in Phase I clinical trial or under development. This update will focus on how the latest developments in Hsp90 biology may better inform the clinical development of Hsp90 inhibitors.