Protein misfolding causes a phenotype of disorders that is modulated by the action of multi-complexes formed by molecular chaperones and the proteasome machine. Hsp90 is a molecular chaperone involved in maintaining folding, stability and function of many proteins involved in apoptosis, signal-transduction pathways and cell-cycle regulation. Many of these proteins are usually deregulated in cancers and by keeping them active Hsp90 helps the stabilization of tumorogenic cells. Therefore, inhibition of Hsp90 will result in degradation of its client proteins via the proteasome followed by a down regulation of several properties of the malignant phenotype. As a consequence, Hsp90 has been considered to be an appealing target for cancer therapeutics because its inhibition can affect multiple oncogenic pathways simultaneously. Major efforts have generated Hsp90 inhibitors that passed Phase I clinical trials and have entered Phase II trials. Furthermore, other compounds are in development to improve efficacy as antitumor agents. In conclusion, the development of Hsp90 inhibitors is considered to be a good example of medicinal chemistry. Specific important aspects of Hsp90 structure and function, the role of the chaperone in cancer and the development of Hsp90 inhibitors that causes growth arrest and apoptosis in cancer cells are discussed.
Keywords: medicinal chemistry, antitumor drugs, geldanamycin, cancer therapeutics, molecular chaperone, Hsp90 inhibitors
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