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Targeting multiple signal transduction pathways through inhibition of Hsp90

Hong Zhang1, Francis Burrows

  • 1Department of Biology, Conforma Therapeutics Corporation, 9393 Towne Centre Dr., 92121, San Diego, CA 92121, USA.

Journal of Molecular Medicine (Berlin, Germany)
|May 29, 2004
PubMed

Insights

Heat shock protein 90 (Hsp90) is crucial for cancer cell survival by stabilizing key oncogenic proteins. Inhibiting Hsp90 leads to client protein degradation, offering a promising therapeutic strategy for various tumors.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • The heat shock protein 90 (Hsp90) complex is essential for the maturation and stability of numerous client proteins, including those vital for oncogenesis such as EGF-R, Her-2, AKT, Raf, p53, and cdk4.
  • Under normal conditions, these client proteins form complexes with Hsp90 and cochaperones to achieve active conformations or enhanced stability.
  • Inhibition of Hsp90 function disrupts these complexes, leading to proteasome-dependent degradation of client proteins and the interruption of critical tumor progression and survival pathways.

Purpose of the Study:

  • To investigate the role of Hsp90 in cancer biology and its potential as a therapeutic target.
  • To identify and characterize Hsp90 inhibitors for cancer treatment.
  • To understand the differential utilization of Hsp90 by tumor cells compared to normal cells.

Main Methods:

  • In vitro and in vivo studies to assess Hsp90 inhibition.
  • Clinical trials of advanced Hsp90 inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (AAG).
  • Analysis of Hsp90 client protein interactions and degradation pathways.

Main Results:

  • Hsp90 inhibition leads to the degradation of multiple oncoprotein clients, simultaneously disrupting critical cancer signaling pathways.
  • The Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (AAG) is currently in phase I/II clinical trials.
  • Tumor cells exhibit distinct Hsp90 utilization compared to normal cells, underpinning the observed drug selectivity.

Conclusions:

  • Hsp90 plays a central role in malignant progression, making it a validated target for cancer therapy.
  • Small molecule Hsp90 inhibitors are valuable tools for elucidating Hsp90 biology and identifying new client proteins.
  • Hsp90 inhibitors demonstrate significant therapeutic promise for treating a variety of cancers.

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