ACTIVATED DROSOPHILA RAS1 IS SELECTIVELY SUPPRESSED BY ISOPRENYL TRANSFERASE INHIBITORS

Ras CAAX (C = cysteine, A = aliphatic amino acid, and X = any amino ac id) peptidomimetic inhibitors of farnesyl protein transferase suppress Ras-dependent cell transformation by preventing farnesylation of the Ras oncoprotein. These compounds are potential anticancer agents for t umors associated with Ras mutations. The peptidomimetic FTI-254 was te sted for Ras1-inhibiting activity in whole animals by injection of act ivated Ras1(val12) Drosophila larvae. FTI-254 decreased the ability of Ras1(val12) to form supernumerary R7 photoreceptor cells in the compo und eye of transformed flies. In contrast, it had no effect on the rel ated supernumerary R7 phenotypes of flies transformed with either the activated sevenless receptor tyrosine kinase, Raf kinase, or a chimeri c Ras1(val12) protein that is membrane associated through myristylatio n instead of isoprenylation. Therefore, FTI-254 acts as an isoprenylat ion inhibitor to selectively inhibit Ras1(val12) signaling activity in a whole-animal model system.