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Updated: Aug 12, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Selective inhibition of farnesyl-protein transferase blocks ras processing in vivo

J B Gibbs1, D L Pompliano, S D Mosser

  • 1Department of Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486.

The Journal of Biological Chemistry
|April 15, 1993
PubMed

Insights

Farnesyl-protein transferase (FPTase) inhibitors may block tumor growth by preventing Ras protein activation. (alpha-hydroxyfarnesyl)phosphonic acid successfully inhibited Ras processing in cells, demonstrating a potential therapeutic strategy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Ras oncogene product requires post-translational modification for biological activity.
  • Farnesylation is a critical modification for Ras protein activation and cell transformation.
  • Inhibitors of farnesyl-protein transferase (FPTase) may block ras-dependent tumorigenesis.

Purpose of the Study:

  • To identify and evaluate inhibitors of farnesyl-protein transferase (FPTase).
  • To assess the efficacy of FPTase inhibitors in blocking Ras protein processing in vivo.

Main Methods:

  • Three structural classes of FPTase inhibitors were synthesized and characterized: (alpha-hydroxyfarnesyl)phosphonic acid, chaetomellic acids, and zaragozic acids.
  • Inhibitor activity was assessed against FPTase and geranylgeranyl-protein transferases.
  • Compounds were tested for inhibition of Ras processing in Ha-ras-transformed NIH3T3 fibroblasts.

Main Results:

  • (alpha-hydroxyfarnesyl)phosphonic acid competitively inhibited FPTase with respect to farnesyl diphosphate.
  • This compound also inhibited Ras processing in Ha-ras-transformed NIH3T3 fibroblasts at 1 microM concentration.
  • Chaetomellic acids and zaragozic acids showed weaker inhibition of FPTase and did not inhibit Ras processing in the cellular assay.

Conclusions:

  • Small organic chemicals selected for FPTase inhibition can effectively block Ras processing in vivo.
  • (alpha-hydroxyfarnesyl)phosphonic acid represents a promising lead compound for targeting ras-dependent tumorigenesis.

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