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Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor

N E Kohl1, S D Mosser, S J deSolms

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

Science (New York, N.Y.)
|June 25, 1993
PubMed

Insights

A novel farnesyl protein transferase (FPTase) inhibitor, L-731,734, selectively blocks Ras oncoprotein processing. This drug candidate shows promise for treating cancers driven by Ras mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Ras oncoprotein activation requires farnesylation, a modification catalyzed by farnesyl protein transferase (FPTase).
  • FPTase inhibitors are explored as anticancer agents, particularly for Ras-dependent tumors.

Purpose of the Study:

  • To evaluate the efficacy of a novel FPTase inhibitor, L-731,734, in blocking Ras processing and cellular transformation.

Main Methods:

  • In vitro testing of L-731,735 as a selective FPTase inhibitor.
  • Inhibition of Ras processing in v-ras-transformed cells using the prodrug L-731,734.
  • Assessing colony formation in soft agar for v-ras, v-raf, and v-mos transformed cells.

Main Results:

  • L-731,735 demonstrated potent and selective inhibition of FPTase in vitro.
  • L-731,734 effectively inhibited Ras processing in v-ras-transformed cells.
  • L-731,734 significantly reduced soft agar colony formation in v-ras-transformed cells, but not in v-raf or v-mos transformed cells.

Conclusions:

  • Synthetic organic FPTase inhibitors can selectively target Ras-dependent cell transformation.
  • L-731,734 represents a promising lead compound for developing targeted anticancer therapies for Ras-driven cancers.

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