By inhibition of such biological targets, it should be possible to disrupt multiple pathways while simultaneously achieving tumor cell specificity. Hsp90 consists of four domains, an Nterminal ATPbinding site, a HDAC middle domain that is an ATP hydrolysisregulating domain, a charged region, and a Cterminal homodimerization domain . The Cterminal end also regulates ATPase activity and is involved in the recruitment of cochaperones. There have been five isoforms of Hsp90 identified so far, including HSP90α, HSP90β, endoplasmic reticulum localized glucose regulated protein 94 , mitochondrial tumor necrosis factor receptorassociated protein 1 , and the recently described membraneassociated HSP90N .
The importance of the different isoforms and their expression in different tumor types is still not well understood, but this potentially has important implications for the different inhibitors of Hsp90 that may selectively target a particular isoform over another, demonstrating improved or reduced Gefitinib effectiveness in certain tumors. Numerous reports exist in the literature, which describe the expression of Hsp90 in various malignancies, although only recently have reports begun to appear looking at specific isoforms of Hsp90 and their relationship to various malignancies. The expression of Hsp90 and its various isoforms has potentially important implications as predictors of outcome, as well as very specific targets for therapy. The NTerminal Inhibitors The first known inhibitors of N terminus of Hsp90 were the naturally occurring products geldanamycin and radiciol .
Early experiments demonstrated that the binding of these agents to Hsp90 resulted in the degradation of the client protein vsrc . Further experiments using these agents have shown that it is the result in the degradation of a large number of client proteins involved in oncogenic pathways . Radiciol caused by its metabolism has essentially no in vivo activity and thus is prokaryotic not a clinically viable agent. Geldanamycin does have potent in vivo activity but has significant toxicity unrelated to its inhibition of Hsp90. Furthermore, its difficult chemical synthesis hampered its development. The production of two geldanamycin analogues, 17 allylamino17demethoxygeldanamycin and 17 dimethylaminoethylamino 17demethoxygeldanamycin improved upon the toxicity associated with geldanamycin and resulted in significantly improved chemical synthesis processes .
As a result these were some of the first Nterminal inhibitors of Hsp90 to be used in clinical trials. However, they continue to be plagued by a series of problems including poor solubility, hepatotoxicity, and the development of resistance. Recently, theories have emerged that address the development of resistance and the lack of effectiveness of 17AAG and 17DMAG as single agents in clinical trials . Resistance to HSP90 inhibitors primarily results from the induction of a heat shock response, namely Hsp27, and Hsp70, which are antiapoptotic factors that have themselves been explored for anticancer targets. This HSP induction is primarily thought to be mediated through hsf1 signaling as it is released and activated from the HSP90 heteroprotein complex upon Nterminal HSP90 inhibition.