DEVELOPMENT OF INHIBITORS OF PROTEIN FARNESYLATION AS POTENTIAL CHEMOTHERAPEUTIC-AGENTS

Protein prenylation, adding either the 15-carbon isoprenoid farnesyl o r the 20-carbon isoprenoid geranylgeranyl to cysteine residue(s) at or near the C-termini of proteins, is a recently identified post-transla tional modification that localizes some proteins to a membrane compart ment. One of the most intensely studied prenylated proteins is Pas, a low molecular weight GTP-binding protein that plays an important role in the regulation of cell proliferation. Proteins encoded by ras genes with oncogenic mutations are capable of transforming cells in culture . Such mutated ras genes are frequently found in a wide variety of hum an tumors. Localization of the Pas oncoprotein to the cytoplasmic face of the plasma membrane via farnesylation is essential for efficient c ell transforming ability. Thus, inhibition of the Pas farnesylation re action is a possible anti-cancer strategy. Several strategies have bee n employed to inhibit Pas farnesylation, including inhibition of isopr enoid biosynthesis and inhibition of the enzyme which catalyzes the fa rnesylation reaction, farnesyl-protein transferase (FPTase). Inhibitor s of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate Limitin g enzyme in isoprenoid biosynthesis, inhibit Ras famesylation and bloc k the growth of ras-transformed cells. However, antiproliferative effe cts do not result from specific inhibition of Ras farnesylation; they are also observed in cells transformed by raf, which is independent of Pas farnesylation. A more specific approach to inhibiting Pas farnesy lation is to inhibit FPTase. Using random screening of natural product s and a rational design approach, a variety of compounds that specific ally inhibit FPTase have been isolated. Several of these compounds wer e found to block the farnesylation of Ras proteins in cell culture and were able to block the anchorage-independent growth of ras-transforme d cells and human tumor cell lines. FPTase inhibitors also blocked the morphologic alteration associated with ras-induced transformation of mammalian cells. In contrast, these compounds did not affect the growt h or morphology of cells transformed by the raf or mos oncogenes, whic h do not require farnesylation to achieve biological activity. Further more,these compounds suppressed the growth of tumors arising from ras- transformed cells in nude mice in the absence of systemic toxicity. Co ntrol tumors formed by raf- or mos-transformed cells were not affected by these compounds. These studies suggest that FPTase inhibitors migh t be safe and effective chemotherapeutic agents. (C) 1995 Wiley-Liss, Inc.