Protein prenylation is increasingly recognized as an important mechanism by which functional association of proteins t o membranes is mediated. Ras proteins, regulators of cell proliferation and differentiation, are among the proteins that undergo farnesylation, one of the two prenylation modifications known. Since ras proteins are activated into hyperactive oncogenic versions in a wide variety of human cancers, agents that d o w n modulate ras activity could be antineoplastic. Therefore, inhibitors of farnesyltransferase have the potential t o be of therapeutic value as anticancer agents due t o their ability t o block ras processing and hence its function. W e describe the identification of two farnesyl pyrophosphate (FPP) analogs that are potent and selective inhibitors of farnesyltransferase. While showing n o toxicity t o untransformed cells, a pivaloyloxyrnethyl ester of one of these inhibitors blocked ras mediated transformation of NIH 3T3 cells. In addition, both the ester and its parent acid inhibited ras farnesylation as measured by incorporation of labeled mevalonate into ras proteins in whole cells. Thus, this i s the first report of an FPP analog t o show biological activity by inhibiting ras processing i n whole cells. (0 1995 Wile"-Liss, Inc.