In the last decade, the molecular chaperone HSP90 has emerged as an important target in cancer therapeutics and has subsequently become the focus of several drug discovery and development efforts. The first-in-class HSP90 inhibitor 17-AAG entered into Phase I clinical trial in 1999. Today 13 HSP90 inhibitors representing multiple drug classes, with different modes of action, are undergoing clinical evaluation.
Hsp90 is the most abundant heat shock protein and represents 1-2% of total cellular proteins in unstressed cells. It is unique from the other chaperones in that it does not play a major role in de novo polypeptide folding. Instead, it regulates post-translational maturation of many conformationally unstable substrates or client proteins, many of which are involved in oncogenesis.