There has been significant learning from studies of the basic biology of Hsp90, as well as translational drug development involving this chaperone, enhanced by the use of Hsp90 inhibitors as chemical probes. Here, we review the discovery and development of Hsp90 inhibitors and assess their potential. Many optimized synthetic, small-molecule Hsp90 inhibitors from diverse chemotypes are now in clinical trials. Preclinical data obtained with these natural products have heightened interest in Hsp90 as a drug target, and 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) has shown clinical activity (as defined by Response Evaluation Criteria in Solid Tumors) in HER2+ breast cancer. Investigators established Hsp90′s druggability using the natural products geldanamycin and radicicol, which mimic the unusual ATP structure adopted in the chaperone's N-terminal nucleotide-binding pocket and cause potent and selective blockade of ATP binding/hydrolysis, inhibit chaperone function, deplete oncogenic clients, and show antitumor activity. Originally viewed with skepticism, Hsp90 inhibitors are now being actively pursued by the pharmaceutical industry, with 17 agents having entered clinical trials. Heat shock protein (Hsp) 90 is an ATP-dependent molecular chaperone that is exploited by malignant cells to support activated oncoproteins, including many cancer-associated kinases and transcription factors, and it is essential for oncogenic transformation.
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