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Related Experiment Videos

17AAG: low target binding affinity and potent cell activity--finding an explanation.

Gabriela Chiosis1, Henri Huezo, Neal Rosen

  • 1Program in Cell Biology and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. chiosisg@mskcc.org

Molecular Cancer Therapeutics
|February 18, 2003
PubMed
Summary

Geldanamycin (GM) and 17AAG show potent anticancer activity by targeting heat shock protein 90. Their true efficacy, however, is linked to higher intracellular concentrations in the micromolar range, not the observed nanomolar activity.

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Oncology

Background:

  • Ansamycin geldanamycin (GM) and its derivative 17AAG exhibit potent anticancer activity against various cancer cells at nanomolar concentrations.
  • These drugs primarily target the molecular chaperone heat shock protein 90 (Hsp90).

Purpose of the Study:

  • To investigate the discrepancy between the high antitumor potency of GM and 17AAG and their relatively low binding affinity to Hsp90.
  • To elucidate the role of physicochemical properties in cellular accumulation and drug efficacy.

Main Methods:

  • Analysis of drug-target interactions and binding affinities.
  • Cellular uptake studies to determine intracellular drug concentrations.
  • Correlation of in vitro potency with in vivo relevant concentrations.

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Main Results:

  • A significant difference was observed between the nanomolar potency and the micromolar Hsp90 binding affinity of GM and 17AAG.
  • Physicochemical characteristics of ansamycins facilitate intracellular accumulation, leading to higher concentrations than initially predicted.
  • The actual antitumor activity correlates with Hsp90 binding affinity in the low micromolar range.

Conclusions:

  • The apparent low nanomolar activity of ansamycins is influenced by cellular accumulation, with true efficacy linked to micromolar concentrations.
  • Achieving therapeutic antitumor effects in patients with 17AAG requires accumulation of micromolar concentrations within tumor cells, mirroring in vitro observations.