Hsp90 inhibitors as selective anticancer drugs

Abstract

Extract: Cancer drug discovery has traditionally focused on targeting DNA synthesis and cell division, resulting in drugs that show efficacy but have severe side effects, due to their lack of selectivity for tumor cells over normal cells. One truly tumor-specific protein, the mutant kinase BCR-ABL, single-handedly causes chronic myelogenous leukemia and is the target of the remarkably effective new drug Gleevec. However, BCR-ABL is very much the exception. The majority of new molecularly-targeted drugs, such as kinase inhibitors, aim to exploit the overexpression of a particular kinase in the tumors compared to the normal tissues. However, the pitfall in doing that is that these drugs are aimed at single biological targets, while the vast majority of advanced tumors harbor multiple genetic alterations that drive malignant growth. A newly emerging class of drugs, called heat shock protein 90 (Hsp90) inhibitors, can simultaneously destroy multiple tumor-causing proteins and also have a profound therapeutic selectivity for tumor cells over normal cells. Hsp90 belongs to a family of proteins called molecular chaperones that are involved in the stabilization and folding of many signaling proteins (collectively referred to as Hsp90 "clients") that are dysregulated in cancers. Hsp90 client proteins include key regulators of cell proliferation and survival such as receptor tyrosine kinases, metastable/mutant signaling proteins, transcription factors and cell cycle regulators (Table 1). Hsp90 client proteins are major components of mitogenic signaling pathways that drive cellular proliferation and survival signaling pathways that counteract programmed cell death (apoptosis). Thus, Hsp90 inhibition can concurrently destablize many oncoproteins in numerous signaling pathways, suggesting that Hsp90 inhibitor drugs would be advantageous in destroying cancer cells that can easily overcome the inhibition of a single target or pathway.