Heat-shock protein 90 inhibitors as antitumor agents: a survey of the literature from 2005 to 2010

Abstract

Introduction: Heat-shock protein 90 (Hsp90) is a validated novel anticancer target with unique features. As a molecular chaperone, Hsp90 is implicated in maintaining the conformation, stability, activity and cellular localization of several key oncogenic client proteins that are involved in signal transduction pathways leading to proliferation, cell-cycle progression, apoptosis, angiogenesis and metastasis. As a result, inhibitors of Hsp90 achieve their promising anticancer activity through disruption of the Hsp90 protein function, thereby freezing the chaperone cycle; this in turn decreases the affinity of Hsp90 for client proteins, thus leading to proteasome-mediated degradation of oncogenic client proteins within cancer cells.

Areas covered: This review provides recent background information on Hsp90 inhibitors. It also highlights a panel of compounds of interest reported in patents and discusses the clinical results of the promising drug candidates.

Expert opinion: In the past 5 years, Hsp90 inhibitors have remained the focus of much interest as new potential anticancer agents. A large variety of scaffolds were studied in both academia and industry. Consequently, these significant research efforts have provided several promising drug candidates for further clinical development. Further progress in the development of Hsp90 inhibitors, combined with a deeper understanding of the chaperon characteristics, strengthens their promise in cancer therapy.

Keywords:

• antitumor agents
• cancer
• client proteins degradation
• heat-shock protein 90
• Hsp90 inhibitors
• neurodegenerative diseases
• proteasome

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