Inhibitors of the HSP90 molecular chaperone: current status.

摘要: The molecular chaperone heat shock protein 90 (HSP90) has emerged as an exciting target for cancer therapy. It operates part of a multichaperone complex and is essential the conformation, stability, function several key oncogenic client proteins such mutant p53, ERBB2, B-RAF, C-RAF, CDK4. HSP90-based machine driven by hydrolysis ATP ADP/ATP nucleotide exchange. Many inhibitors HSP90 interrupt intrinsic ATPase activity, causing degradation via ubiquitin-proteasome pathway. first-in-class inhibitor in clinical trials geldanamycin analog, 17-allylamino, 17-demethoxygeldanamycin (17-AAG). results that have from these been encouraging, with stable disease observed two melanoma patients. Pharmacodynamic endpoints, induction HSP70 downregulation C-RAF CDK4 peripheral blood mononuclear cells tumor biopsies treated patients, provided evidence inhibition at well-tolerated doses. toxicity 17-AAG mild. Several preclinical studies shown may enhance efficacy variety chemotherapeutic agents. Phase II various cancers initiated well I combined therapy 17-AAG. However, there are limitations solubility, hepatotoxicity. Thus, it not surprising new agents under development against this novel show promise.