title: Protein farnesyltransferase inhibitors block the growth of ras-dependent tumors in nude mice.
abstract: The posttranslational addition of a farnesyl moiety to the Ras oncoprotein is essential for its transforming activity. Cell-active inhibitors of the enzyme that catalyzes this reaction, protein farnesyltransferase, have been shown to selectively block ras-dependent transformation of cells in culture. Here we describe the protein farnesyltransferase inhibitor 2(S)-[2(S)-[2(R)-amino-3-mercapto]propylamino-3(S)-methyl] pentyloxy-3-phenylpropionylmethioninesulfone methyl ester (L-739,749), which suppressed the anchorage-independent growth of Rat1 cells transformed with viral H-ras and the human pancreatic adenocarcinoma cell line PSN-1, which harbors altered K-ras, myc, and p53 genes. This compound also suppressed the growth of tumors arising from ras-transformed Rat1 cells in nude mice by 66%. Under the same conditions, doxorubicin inhibited tumor growth by 33%. Control tumors formed by v-raf- or v-mos-transformed Rat1 cells were unaffected by L-739,749. Furthermore, mice treated with L-739,749 exhibited no evidence of systemic toxicity. This is a demonstration of antitumor activity in vivo using a synthetic small molecule inhibitor of protein farnesyltransferase.
authors.affiliation: Department of Cancer Research, Merck Research Laboratories, West Point, PA 19486.
authors.forename: N E
authors.initials: NE
authors.lastname: Kohl
authors.forename: F R
authors.initials: FR
authors.lastname: Wilson
authors.forename: S D
authors.initials: SD
authors.lastname: Mosser
authors.forename: E
authors.initials: E
authors.lastname: Giuliani
authors.forename: S J
authors.initials: SJ
authors.lastname: deSolms
authors.forename: M W
authors.initials: MW
authors.lastname: Conner
authors.forename: N J
authors.initials: NJ
authors.lastname: Anthony
authors.forename: W J
authors.initials: WJ
authors.lastname: Holtz
authors.forename: R P
authors.initials: RP
authors.lastname: Gomez
authors.forename: T J
authors.initials: TJ
authors.lastname: Lee
mesh_terms: D019883:Alkyl and Aryl Transferases; D000818:Animals; D002472:Cell Transformation, Viral; D016258:Genes, mos; D011905:Genes, ras; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000494:pharmacology*; D014166:Transferases / Q000037:antagonists & inhibitors*
chemical_list: C089417:L 739750; D009842:Oligopeptides; C087363:L 739749; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase