CHAPTER 18:Allosteric Modulators of Heat Shock Protein 90 (HSP90)

Heat shock proteins (HSP) are a family of molecular chaperones that are the most conserved proteins present in both prokaryotes and eukaryotes. HSPs facilitate numerous events in cellular physiology including: protein recycling, transportation, migration, post-translational modification, and the regulation of signalling pathways. The molecular chaperone heat shock protein 90 (HSP90) plays a particularly important role in maintaining homeostasis. As a highly conserved molecular chaperone, HSP90 is an abundant and ubiquitously expressed protein, constituting 1–2% of total cellular protein in normal cells. In order to protect mutated and over-expressed oncoproteins from degradation, HSP90 increases to 3–6% of overall protein in cancerous cells. HSP90 is also a key regulator of the stress response, in part because it folds, maintains, and stabilizes over 400 client proteins, many of which are involved in cancer cell growth. This chapter compares and contrasts three classes of allosteric inhibitors. The first class are compounds targeting the ATP binding site at the N-terminus of HSP90 (classical inhibitors), while impacting clients that bind to the middle domain. The second class are those that bind to the C-terminus, which have anti-cancer cellular activity without inducing high levels of HSF-1, HSP70, or HSP27. The third class are the SM series, binding between the N- and middle domains of HSP90 but impacting the C-terminus. Progress made and challenges associated with each class of ligands are discussed.