SELECTIVE-INHIBITION OF RAS-DEPENDENT TRANSFORMATION BY A FARNESYLTRANSFERASE INHIBITOR

To acquire transforming potential, the precursor of the Ras oncoprotei n must undergo farnesylation of the cysteine residue located in a carb oxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes th is modification, farnesyl protein transferase (FPTase), have therefore been suggested as anticancer agents for tumors in which Ras contribut es to transformation. The tetrapeptide analog L-731,735 is a potent an d selective inhibitor of FPTase in vitro. A prodrug of this compound, L-731,734, inhibited Ras processing in cells transformed with v-ras. L -731,734 decreased the ability of v-ras-transformed cells to form colo nies in soft agar but had no effect on the efficiency of colony format ion of cells transformed by either the v-raf or v-mos oncogenes. The r esults demonstrate selective inhibition of ras-dependent cell transfor mation with a synthetic organic inhibitor of FPTase.