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The post-translational addition of a farnesyl moiety to the Ras oncoprotein is essential for its membrane localization and is required for both its biological activity and ability to induce malignant transformation. The present invention describes design and synthesis of a farnesylpyrophosphate (FPP) analog, 8-anilinogeranyl pyrophosphate (AGPP) that is transferred to Ras by farnesyltransferase (FTase), in which the ω-terminal isoprene unit of the farnesyl group has been replaced with an aniline functionality. AGPP potently inhibited FTase activity in vitro (IC50=0.6 μM) and is highly selective showing little inhibitory activity against either geranylgeranyl-protein transferase type I (GGTase I) (IC50=31 μM) or the utilization of FPP by the enzyme squalene synthase (IC50=1000 μM). Kinetic analyses suggest that AGPP acts as a competitive inhibitor of FTase with respect to FPP. In vitro studies using [3H]AGPP show that the analog was appropriately transferred by FTase to Ras. Derivitization of AGPP with a bulky iodo group on the aniline ring does not significantly alter its biochemical properties. These data indicate that the modified molecules are the first truly transferable analogs of FPP and open the door to additional analogs to probe the biological function of protein farnesylation.


University of Kentucky Research Foundation, Lexington, KY (US)

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