site of malignancy. This concept requires further attention as it may explain the correlation of increased levels of Hsp90A in the plasma of patients with advanced stages of malignancy. Hsp90 Inhibitors Hsp90 is exploited by cancer cells to support activated oncoproteins, including many kinases and transcription factors. These clients are often mutated, amplified or translocated in malignancy, and Hsp90 works to buffer these cellular stresses induced by malignant transformation. Inhibition of Hsp90 leads to the degradation or instability of many of its client proteins. Thus, Hsp90 has become an attractive target for cancer therapy. As with all ATPases, ATP binding and hydrolysis is essential for the chaperoning function of Hsp90 in vivo. Hsp90 inhibitors interfere with this cycle at its early stages by replacing ATP, leading to the regulated ubiquitination and proteasome-mediated degradation of most client proteins. As such, the nucleotide binding pocket remains that most amenable to inhibitor generation. To date, there are 23 active Hsp90 inhibitor oncology trials, and 13 HSP90 inhibitors are currently undergoing clinical evaluation in cancer patients, 10 of which have entered the clinic in the past few years. While the N-terminal nucleotide-binding pocket of Hsp90 is most widely studied and thus targeted, recent studies have suggested that a second ATP-binding site is located in the Hsp90 C-terminus. Targeting of this region has resulted in specific reduced Hsp90-hormone interactions and has been shown to influence Hsp90 nucleotide binding. Although none of the C-terminal Hsp90 inhibitors have yet to enter the clinic, the use of both N- and C-terminal Hsp90 inhibitors in combination represents an exciting new strategy for chemotherapy. Although many of the afore-mentioned inhibitors share the same Hsp90 binding site (either N- or C-terminal), it has been shown that some of these drugs preferentially access distinct Hsp90 populations, which are differentiated by the extent of their post-translational modification. Though no published inhibitor has yet to distinguish between Hsp90A and Hsp90B, a recent study has shown that phosphorylation of a particular residue in the Hsp90 N-terminus can provide isoform specificity to inhibitor binding., thus providing an additional level of regulation for optimal Hsp90 targeting. Notes References Further reading External links