Abstract
The ATP-dependent molecular chaperone heat shock protein 90 (HSP90) is required for the function and stability of an increasing number of oncogenic proteins. HSP90 chaperones these proteins by forming a series of multimeric complexes to facilitate client protein loading, activation and release, a process which is driven by ATP hydrolysis. Many HSP90 client proteins have been implicated in the development and progression of cancer. As a result of this, HSP90 has emerged as an exciting drug target in oncology. Of particular benefit, HSP90 inhibitors have the potential to simultaneously deplete multiple proteins involved in all the six hallmark traits of cancer. The initial approach taken to modulate HSP90 was to focus on inhibiting the ATPase activity, resulting in degradation of client proteins via the ubiquitin proteasome pathway. Several chemical classes of compounds which target the ATP binding pocket of HSP90 have shown anti-cancer activity in preclinical models. The geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) is now undergoing phase II studies. The results from phase I trials have shown clear evidence of target modulation and an indication of clinical activity in melanoma, prostate, renal, multiple myeloma and trastuzumab-refractory breast cancers. These data have provided proof-of-principle that HSP90 is a promising drug target in cancer. A number of new synthetic small molecule inhibitors are currently undergoing development. This review will focus on the current status of the ATP-competitive HSP90 inhibitors as well as novel approaches to inhibit the HSP90 chaperone machine
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