title: Stringent structural requirements for anti-Ras activity of S-prenyl analogues.
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, farnesoic acid, N-acetyl-S-farnesyl-L-cysteine and S-farne-sylthiopropionic 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 substitutents 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.
authors.affiliation: Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Israel.
authors.forename: Z
authors.initials: Z
authors.lastname: Aharonson
authors.forename: M
authors.initials: M
authors.lastname: Gana-Weisz
authors.forename: T
authors.initials: T
authors.lastname: Varsano
authors.forename: R
authors.initials: R
authors.lastname: Haklai
authors.forename: D
authors.initials: D
authors.lastname: Marciano
authors.forename: Y
authors.initials: Y
authors.lastname: Kloog
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003545:Cysteine / Q000031:analogs & derivatives / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005204:Farnesol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012459:Salicylates / Q000737:chemistry* / Q000494:pharmacology*; D014162:Transfection; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; C057785:S-farnesylcysteine; D018631:ras Proteins; D003545:Cysteine