Development of Farnesyltransferase Inhibitors as Potential Antitumor Agents

Activating mutations of the ras genes are among the more common genetic aberrations known in human cancers, particularly in pancreatic and colon carcinomas (1). Three highly homologous members of the ras protooncogene family have been identified in higher mammals; H-ras, K-ras, and N-ras (2). All three ras genes code for proteins that end in a sequence called the “CAAX box,” which is the recognition sequence for post-translational farnesylation (3). Farnesylation is catalyzed by farnesyltransferase (FTase), a cytosolic enzyme that utilizes farnesyl pyrophosphate (FPP) as a farnesyl donor to modify the cysteine residue of the ras CAAX terminus (4). Anchoring of the Ras proteins to the inner surface of the plasma membrane is required for normal functions in signal transduction as well as for transforming activities and signaling would not occur when farnesylation is blocked (5). Although farnesylation is not entirely specific for Ras proteins, only a few other cellular proteins undergo this posttranslational modification (6,7). Our goal has been to develop potent and selective inhibitors of FTase in an attempt to inhibit and/or reverse Ras-mediated malignant transformation in rodent and human cancers, in cell culture as well as in animal models and ultimately in humans.