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Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
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Hsp90 inhibitors as anti-cancer agents, from basic discoveries to clinical development

Shiro Soga1, Shiro Akinaga, Yukimasa Shiotsu

  • 1Research Division and Development Division, Kyowa Hakko Kirin Co., Ltd., Japan.

Current Pharmaceutical Design
|August 28, 2012
PubMed

Insights

Heat shock protein 90 (Hsp90) inhibitors are crucial for cancer therapy, stabilizing oncogenic kinases. Newer Hsp90 inhibitors show promise in clinical trials, advancing cancer treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone.
  • Hsp90 stabilizes essential oncogenic kinases like HER2, EGFR, BCR-ABL, B-Raf, and EML4-ALK, crucial for tumor growth.
  • Over 200 Hsp90 client proteins have been identified, many vital for cancer transformation.

Purpose of the Study:

  • To review the discovery of major Hsp90 client proteins in cancer using radicicol (RD) derivatives.
  • To detail the history of KW-2478 discovery and development.
  • To provide an update on the clinical trial status of novel Hsp90 inhibitors.

Main Methods:

  • Review of previous reports on Hsp90 client protein discovery.
  • Analysis of Hsp90 inhibitor development, including geldanamycin (GA) and radicicol (RD) derivatives.
  • Examination of clinical trial data for second-generation Hsp90 inhibitors.

Main Results:

  • First-generation Hsp90 inhibitors faced limitations in physicochemical properties and safety.
  • Over 200 Hsp90 client proteins have been identified, aiding in cancer drug discovery.
  • More than 10 novel, second-generation Hsp90 inhibitors have entered clinical trials, with some demonstrating efficacy.

Conclusions:

  • Hsp90 inhibitors represent a promising therapeutic strategy in oncology.
  • Second-generation Hsp90 inhibitors offer improved profiles and potential clinical benefits.
  • Ongoing research and clinical trials continue to advance Hsp90-targeted cancer therapies.

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