RAS FARNESYLATION AS A TARGET FOR NOVEL ANTITUMOR AGENTS - POTENT ANDSELECTIVE FARNESYL DIPHOSPHATE ANALOG INHIBITORS OF FARNESYLTRANSFERASE

Protein prenylation is increasingly recognized as an important mechani sm by which functional association of proteins to membranes is mediate d. Ras proteins, regulators of cell proliferation and differentiation, are among the proteins that undergo farnesylation, one of the two pre nylation modifications known. Since ras proteins are activated into hy peractive oncogenic versions in a wide variety of human cancers, agent s that down modulate ras activity could be antineoplastic. Therefore, inhibitors of farnesyltransferase have the potential to be of therapeu tic value as anticancer agents due to their ability to block ras proce ssing and hence its function. We describe. the identification of two f arnesyl pyrophosphate (FPP) analogs that are potent and selective inhi bitors of farnesyltransferase. While showing no toxicity to untransfor med cells, a pivaloyloxymethyl ester of one of these inhibitors blocke d ras mediated transformation of NIH 3T3 cells. In addition, both the ester and its parent acid inhibited ras farnesylation as measured by i ncorporation of labeled mevalonate into ras proteins in whole cells. T hus, this is the first report of an FPP analog to show biological acti vity by inhibiting ras processing in whole cells. (C) 1995 Wiley-Liss, Inc.