'Paleontological Institute at The University of Kansas'
Abstract
The 90 kDa heat shock proteins (Hsp90) are critical for the maintenance of cellular homeostasis and mitigate the effects of cellular stress and therefore, play an important role in cell survival. Hsp90, as a molecular chaperone, folds nascent polypeptides and denatured proteins to their biologically relevant conformations. Many of the proteins dependent upon Hsp90 are essential to the growth and proliferation of cancer cells. In fact, proteins associated with all ten hallmarks of cancer are dependent upon the Hsp90 protein folding machinery. Consequently, inhibition of Hsp90 represents a combinatorial approach for the treatment of cancer. 17 small molecule inhibitors of Hsp90 have entered clinical trials, all of which bind Hsp90 N-terminus and exhibit pan-inhibitory activity against the four Hsp90 isoforms: Hsp90, Hsp90, Grp94, and Trap1. However, lack of isoform selectivity with current clinical candidates appears detrimental as more than 20 clinical trials have failed, citing hepatotoxicity, cardiotoxicity, and peripheral neuropathy amongst other side effects. Additionally, pan-inhibition of Hsp90 induces the pro-survival heat shock response, requiring the escalation of patient doses to overcome increased Hsp90 expression. Therefore, alternative approaches for Hsp90 modulation are highly sought after. Isoform-selective inhibition of Hsp90 provides an opportunity to address the aforementioned detriments associated with pan-Hsp90 N-terminal inhibitors. Hydrolysis of ATP by the N-terminal nucleoside binding pocket is required for the maturation of client protein substrates, and all four Hsp90’s share 85% identity within this region. Consequently, the discovery of isoform-selective inhibitors has been challenging. Described herein is the rationale for development of isoform selective inhibitors and the identification of the first isoform selective inhibitors of Hsp90 and Hsp90-isoforms. Unlike the N-terminus, inhibition of the Hsp90 C-terminus does not induce the heat shock response and hence, C-terminal inhibitors manifest the desired cytotoxic affect against cancer cells. However, absence of a co-crystal structure and lack of lead compounds, have resulted in limited success towards the development of Hsp90 C-terminal inhibitors. Recently, EGCG, a green tea polyphenol, was shown to bind at the C-terminus of Hsp90. Structure activity relationships studies were conducted on EGCG for improved Hsp90 inhibition and are also presented