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Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
07:57

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Inhibitors of the HSP90 molecular chaperone: current status

Swee Sharp1, Paul Workman

  • 1Signal Transduction and Molecular Pharmacology Team, Cancer Research UK, Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, SM2 5NG, United Kingdom.

Advances in Cancer Research
|July 25, 2006
PubMed

Insights

Heat shock protein 90 (HSP90) is a key cancer target. Inhibitors like 17-AAG show promise in early trials, degrading oncogenic proteins, but new agents are needed due to limitations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Heat shock protein 90 (HSP90) is crucial for cancer cell survival, stabilizing oncogenic proteins.
  • HSP90 function relies on ATP hydrolysis, making its ATPase activity a therapeutic target.
  • Key oncogenic client proteins dependent on HSP90 include mutant p53, ERBB2, B-RAF, C-RAF, and CDK4.

Purpose of the Study:

  • To evaluate HSP90 as a molecular target in cancer therapy.
  • To assess the efficacy and safety of HSP90 inhibitors, specifically 17-AAG.
  • To explore the potential of HSP90 inhibition in combination therapies.

Main Methods:

  • Clinical trials of the HSP90 inhibitor 17-AAG (geldanamycin analog).
  • Assessment of pharmacodynamic endpoints (HSP70 induction, C-RAF/CDK4 downregulation) in patient samples.
  • Preclinical studies investigating 17-AAG combined with chemotherapeutic agents.

Main Results:

  • Encouraging results from early clinical trials, including stable disease in melanoma patients.
  • Evidence of target engagement and inhibition at well-tolerated doses.
  • 17-AAG demonstrated potential to enhance chemotherapy efficacy in preclinical models.

Conclusions:

  • HSP90 is a validated target for cancer therapy, with 17-AAG showing early clinical promise.
  • Despite mild toxicity and encouraging pharmacodynamics, 17-AAG has limitations (solubility, stability, hepatotoxicity).
  • Development of novel HSP90 inhibitors is ongoing and shows significant potential for cancer treatment.

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