SRc family kinases receptor tyrosine kinases such as erbB1 and human epidermal growth factor receptor 2 , mutant p53, telomerase, the steroid hormone receptors, and mesenchymalepithelial transition JNK Signaling Pathway factor , as well as many others . Thus, the targeting of Hsp90 theoretically represents a powerful tool against a broad array of cancers. This article discusses the data leading to the development of inhibitors of Hsp90 and the results of the clinical trials conducted to date with these inhibitors. Furthermore, we identify some current problems with the inhibition of Hsp90 and discuss new compounds that may help circumvent these problems and enhance enthusiasm for the targeting of Hsp90 as an anticancer therapy.Hsp90 is a ubiquitously expressed protein that plays an essential role in cell signaling, proliferation, and survival.
Eukaryotic Hsp90 is constitutively expressed under normal conditions and significantly overexpressed in cells under stress . Induction of a heat shock response stemming from repeated exposure to an initial insult leads to development of a cytoprotective state in normal tissue that would STI-571 otherwise be lethal to the cell. These stressful conditions include elevated temperature, hypoxia, nonphysiologic pH, nutrient deprivation, and also cancer. The expression of Hsp90 allows cells to survive even in unfavorable conditions such as hypoxia or other conditions created by genetic alterations often associated with tumor cells . It is this property that makes Hsp90 a potentially viable target for anticancer therapies because the inhibition of Hsp90 would lead to an inability to respond to stressors often associated with cancer cells.
In addition, it has been shown that HSP90 from cancer cells prokaryotic has a higher activity and ATPbinding affinity than its latent form found in “normal” cells . This higher affinity potentially allows for selectivity of Hsp90 inhibitors for cancer cells compared with normal cells, thereby resulting in decreased toxicity or side effects to normal cells. As previously mentioned, Hsp90 is required for the folding of polypeptides into their mature and biologically active state. Whereas many traditional agents or even newer targeted agents focus on one specific pathway, the inhibition of Hsp90 may lead to the degradation of proteins involved in all six hallmark pathways of cancer including self sufficiency in growth signals, insensitivity to antigrowth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion metastasis .
Furthermore, these proteins are not restricted to only one tumor type but are variably important in a variety of both solid and nonsolid malignancies . Because multiple pathways are known to be dysfunctional in most cancers, and cancers accumulate new oncogenic mutations as they progress, a single drug is unlikely to be completely effective for successful treatment of most cancers. Consequently, there has been a rapid evolution toward the targeted administration of combination therapies that simultaneously disrupt multiple therapeutic targets. An alternative to the development of combination therapy is the identification of novel biological targets that, when inhibited, antagonize several commonly hijacked oncogenic pathways in malignant.