Stringent structural requirements for anti-Ras activity of S-prenyl analogues

Ziporet Aharonson, Mali Gana-Weisz, Tal Varsano, Roni Haklai, Daniele Marciano, Yoel Kloog

Research output: Contribution to journalArticlepeer-review

Abstract

The carboxy terminal S-farnesylcysteine of Ras oncoproteins is required for their membrane anchorage and transforming activities. We showed previously that S-farnesylthiosalicylic acid (FTS) affects the membrane anchorage of activated H-Ras in EJ cells and inhibits their growth. We report here on structural elements in S-prenyl derivatives that specifically inhibit the growth of EJ cells, but not of untransformed Rat-1 cells. Inhibition of the Ras-dependent extracellular signal-regulated protein kinase (ERK), of DNA synthesis and of EJ cell growth were apparent after treatment with FTS or its 5-fluoro, 5-chloro and 4-fluoro derivatives or with the C20 S-geranylgeranyl derivative of thiosalicylic acid. The 4-Cl-FTS analogue was a weak inhibitor of EJ cell growth. The 3-Cl-FTS analogue and the FTS carboxyl methyl ester were inactive, as were the C10 S-geranyl derivative of thiosalicylic acid, farnesol, farnesoic acid, N-acetyl-S-farnesyl-L-cysteine and S-farnesylthiopropionic acid. The structural requirements for anti-Ras activity of S-prenyl analogues thus appear to be rather stringent. With regard to chain length, the C15 farnesyl group linked to a rigid backbone seems to be necessary and sufficient. A free carboxyl group in an appropriately rigid orientation as in thiosalicylic acid, is also required. Halogenic substituents on the benzene ring of the thiosalicylic acid are tolerated only at position 5 or 4. This information may facilitate the design of potent Ras antagonists and deepen our understanding of the mode of association of Ras with the plasma membrane.

Original languageEnglish
Pages (from-to)40-50
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1406
Issue number1
DOIs
StatePublished - 27 Feb 1998

Keywords

  • EJ cell line
  • Farnesyl analog
  • Geranylgeranyl analog
  • Ras oncoproteins
  • Ras-antagonists

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