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Development of small molecule Hsp90 inhibitors: utilizing both forward and reverse chemical genomics for drug
1Cell and Cancer Biology Branch, National Cancer Institute, NIH, Rockville, MD 20850, USA. len@helix.nih.gov
Abstract:
Heat shock protein 90 (Hsp90) is a molecular chaperone whose association is required for stability and function of multiple mutated, chimeric, and over-expressed signaling proteins that promote cancer cell growth and/or survival. Hsp90 client proteins include mutated p53, Bcr-Abl, Raf-1, Akt, HER2/Neu (ErbB2), and HIF-1alpha. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the destabilization and eventual degradation of Hsp90 client proteins, and they have also shown promising anti-tumor activity in preclinical model systems. One Hsp90 inhibitor, 17-AAG, is currently in Phase I clinical trial. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple signaling pathways on which cancer cells depend for growth and survival. Benzoquinone ansamycin binding to Hsp90 led to the identification of radicicol as an additional Hsp90 inhibitor. Additional target-based screening uncovered novobiocin as a third structurally distinct small molecule with Hsp90 inhibitory properties. Use of novobiocin, in turn, led to identification of a previously uncharacterized C-terminal ATP binding site in the chaperone. Small molecule inhibitors of Hsp90 have been very useful in understanding Hsp90 biology and in validating this protein as a molecular target for anti-cancer drug development.
Insights
Heat shock protein 90 (Hsp90) inhibitors target cancer cell growth by degrading key signaling proteins. These Hsp90 inhibitors show promise for anti-cancer drug development and clinical trials.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Heat shock protein 90 (Hsp90) is a molecular chaperone essential for the stability and function of numerous cancer-promoting signaling proteins.
- Hsp90 client proteins include critical oncogenic factors such as mutated p53, Bcr-Abl, Raf-1, Akt, HER2/Neu (ErbB2), and HIF-1alpha.
Purpose of the Study:
- To explore the potential of Hsp90 inhibitors as anti-cancer therapeutics.
- To validate Hsp90 as a molecular target for cancer drug development.
Main Methods:
- Investigated small molecule inhibitors targeting Hsp90, including 17-AAG, radicicol, and novobiocin.
- Utilized target-based screening and molecular binding studies to identify and characterize Hsp90 inhibitors and their binding sites.
Main Results:
- Hsp90 inhibitors destabilize and promote the degradation of Hsp90 client proteins, thereby inhibiting multiple cancer cell signaling pathways.
- Promising anti-tumor activity was observed in preclinical models.
- Novobiocin identified a novel C-terminal ATP binding site in Hsp90.
Conclusions:
- Hsp90 inhibitors represent a unique therapeutic strategy by simultaneously targeting multiple oncogenic pathways.
- Hsp90 is a validated and promising molecular target for the development of novel anti-cancer drugs.