Selective Inhibition of ras-Dependent Transformation by a Farnesyltransferase Inhibitor

• Published in: Science (American Association for the Advancement of Science) Vol. 260; no. 5116; pp. 1934 - 1937
• Main Authors: Kohl, Nancy E., Mosser, Scott D., deSolms, S. Jane, Giuliani, Elizabeth A., Pompliano, David L., Graham, Samuel L., Smith, Robert L., Scolnick, Edward M., Oliff, Allen, Gibbs, Jackson B.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for the Advancement of Science 25.06.1993; American Association for the Advancement of Science
• Subjects: 3T3 cells; Alkyl and Aryl Transferases; Animals; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biochemistry; Biological and medical sciences; Cell culture techniques; Cell Division - drug effects; Cell growth; Cell Line; Cell membranes; Cell Transformation, Neoplastic - drug effects; Dipeptides - chemistry; Dipeptides - pharmacology; Drug Design; Enzymes; Farnesyltranstransferase; General aspects; Genes, ras; Inhibitory concentration 50; Lactones; Medical sciences; Neoplastic cell transformation; Oncogene Proteins - metabolism; Pharmacology. Drug treatments; Protein Prenylation - drug effects; Proteins; Rats; Transferases - antagonists & inhibitors; Antineoplastic agent; GTP; Enzyme; Gene product; V-Onc gene; Enzyme inhibitor; Cell transformation; Binding protein; Tetrapeptide; Analog; Farnesyltransferase; C-Onc gene; G protein
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.8316833

To acquire transforming potential, the precursor of the Ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase (FPTase), have therefore been suggested as anticancer agents for tumors in which Ras contributes to transformation. The tetrapeptide analog L-731,735 is a potent and 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 colonies in soft agar but had no effect on the efficiency of colony formation of cells transformed by either the v-raf or v-mos oncogenes. The results demonstrate selective inhibition of ras-dependent cell transformation with a synthetic organic inhibitor of FPTase.