Protein prenylation, adding either the 15-carbon isoprenoid farnesyl or the 20-carbon isoprenoid geranylgeranyl to cysteine residuek) at or near the C-termini of proteins, is a recently identified post-translational modification that localizes some proteins to a membrane compartment. One of the most intensely studied prenylated proteins is Ras, a low molecular weight GTP-binding protein that plays an important role in the regulation of cell proliferation. Proteins encoded by rus genes with oncogenic mutations are capable of transforming cells in culture. Such mutated ras genes are frequently found in a wide variety of human tumors. Localization of the Ras oncoprotein to the cytoplasmic face of the plasma membrane via farnesylation is essential for efficient cell transforming ability. Thus, inhibition of the Ras farnesylation reaction is a possible anti-cancer strategy.
Several strategies have been employed to inhibit Ras farnesylation, including inhibition of isoprenoid biosynthesis and inhibition of the enzyme which catalyzes the farnesylation reaction, farnesyl-protein transferase (FPTase). Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate limiting enzyme in isoprenoid biosynthesis, inhibit Ras farnesylation and block the growth of rus-transformed cells. However, antiproliferative effects do not result from specific inhibition of Ras farnesylation; they are also observed in cells transformed by ruf, which is independent of Ras farnesylation. A more specific approach to inhibiting Ras farnesylation is to inhibit FPTase. Using random screening of natural products and a rational design approach, a variety of compounds that specifically inhibit FPTase have been isolated. Several of these compounds were found to block the farnesylation of Ras proteins in cell culture and were able to block the anchorage-independent growth of rus-transformed 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 growth or morphology of cells transformed by the ruf or mos oncogenes, which do not require farnesylation to achieve biological activity. Furthermore, these compounds suppressed the growth of tumors arising from yastransformed cells in nude mice in the absence of systemic toxicity. Control tumors formed by ruf-or mostransformed cells were not affected by these compounds. These studies suggest that FPTase inhibitors might be safe and effective chemotherapeutic agents.