FARNESYLTRANSFERASE INHIBITORS AND ANTI-RAS THERAPY

The oncoprotein encoded by mutant ras genes is initially synthesized a s a cytoplasmic precursor which requires posttranslational processing to attain biological activity; farnesylation of the cysteine residue p resent in the CaaX motif located at the carboxy-terminus of all Ras pr oteins is the critical modification. Once farnesylated and further mod ified, the mature Ras protein is inserted into the cell's plasma membr ane where it participates in the signal transduction pathways that con trol cell growth and differentiation. The farnesylation reaction that modifies Ras and other cellular proteins having an appropriate CaaX mo tif is catalyzed by a housekeeping enzyme termed farnesyl-protein tran sferase (FPTase). Inhibitors of this enzyme have been prepared by seve ral laboratories in an effort to identify compounds that would block R as-induced cell transformation and thereby function as Ras-specific an ticancer agents. A variety of natural products and synthetic organic c ompounds were found to block farnesylation of Ras proteins in vitro. S ome of these compounds exhibit antiproliferative activity in cell cult ure, block the morphological alterations associated with Ras-transform ation, and can block the growth of Ras-transformed cell lines in tumor colony-forming assays. By contrast, these compounds do not affect the growth or morphology of cells transformed by the Raf or Mos oncoprote ins, which do not require farnesylation to achieve biological activity . The efficacy and lack of toxicity observed with FPTase inhibitors in an animal tumor model suggest that specific FPTase inhibitors may be useful for the treatment of some types of cancer.