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

Published on: January 20, 2023

Discovery and development of Hsp90 inhibitors: a promising pathway for cancer therapy

James R Porter1, Christian C Fritz, Kristopher M Depew

  • 1Infinity Pharmaceuticals, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. James.Porter@infi.com

Current Opinion in Chemical Biology
|April 23, 2010
PubMed

Insights

Heat shock protein 90 (Hsp90) inhibitors offer a promising cancer therapy approach by simultaneously targeting multiple oncogenic pathways. Fourteen Hsp90 drug candidates are in clinical trials, with advanced ones in Phase 2.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Heat shock protein 90 (Hsp90) is a crucial chaperone protein regulating the stability and activity of numerous oncoproteins.
  • Targeting Hsp90 offers a potential strategy for combinatorial inhibition of multiple oncogenic signaling pathways.
  • Recent discoveries highlight the need for multi-pronged therapeutic approaches due to feedback loops negating single-agent efficacy.

Purpose of the Study:

  • To review the development and clinical progress of Hsp90 inhibitors as a cancer therapy.
  • To highlight the potential of Hsp90 as a master regulator for simultaneous targeting of multiple cancer pathways.
  • To discuss the challenges and opportunities in advancing Hsp90 inhibitors in clinical trials.

Main Methods:

  • Review of current clinical trials involving Hsp90 inhibitors.
  • Analysis of the chemical diversity and properties of Hsp90 inhibitor drug candidates.
  • Examination of Hsp90 inhibitor pharmacokinetics, including tumor accumulation and clearance from normal tissues.

Main Results:

  • Fourteen Hsp90 inhibitor drug candidates are currently in clinical trials for various cancer indications, as single agents or in combination therapy.
  • These inhibitors exhibit diverse chemical structures but share a common mechanism of binding to the N-terminal ATP pocket of Hsp90.
  • Advanced Hsp90 inhibitors demonstrate tumor-specific accumulation and rapid clearance from normal tissues, suggesting a favorable therapeutic window.

Conclusions:

  • Hsp90 inhibitors represent a promising class of first-in-class therapeutics for cancer treatment.
  • The clinical development of Hsp90 inhibitors is advancing, with several candidates in Phase 2 trials.
  • Key challenges remain in defining the optimal therapeutic window, dosing schedule, and specific indications for Hsp90 inhibitors.

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