title: Benzodiazepine peptidomimetics: potent inhibitors of Ras farnesylation in animal cells.
abstract: Oncogenic Ras proteins transform animal cells to a malignant phenotype only when modified by farnesyl residues attached to cysteines near their carboxyl termini. The farnesyltransferase that catalyzes this reaction recognizes tetrapeptides of the sequence CAAX, where C is cysteine, A is an aliphatic amino acid, and X is a carboxyl-terminal methionine or serine. Replacement of the two aliphatic residues with a benzodiazepine-based mimic of a peptide turn generated potent inhibitors of farnesyltransferase [50 percent inhibitory concentration (IC50) < 1 nM]. Unlike tetrapeptides, the benzodiazepine peptidomimetics enter cells and block attachment of farnesyl to Ras, nuclear lamins, and several other proteins. At micromolar concentrations, these inhibitors restored a normal growth pattern to Ras-transformed cells. The benzodiazepine peptidomimetics may be useful in the design of treatments for tumors in which oncogenic Ras proteins contribute to abnormal growth, such as that of the colon, lung, and pancreas.
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235.
authors.forename: G L
authors.initials: GL
authors.lastname: James
authors.forename: J L
authors.initials: JL
authors.lastname: Goldstein
authors.forename: M S
authors.initials: MS
authors.lastname: Brown
authors.forename: T E
authors.initials: TE
authors.lastname: Rawson
authors.forename: T C
authors.initials: TC
authors.lastname: Somers
authors.forename: R S
authors.initials: RS
authors.lastname: McDowell
authors.forename: C W
authors.initials: CW
authors.lastname: Crowley
authors.forename: B K
authors.initials: BK
authors.lastname: Lucas
authors.forename: A D
authors.initials: AD
authors.lastname: Levinson
authors.forename: J C
authors.initials: JC
authors.lastname: Marsters
mesh_terms: D019883:Alkyl and Aryl Transferases; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D006224:Cricetinae; D015195:Drug Design; D051231:Farnesyltranstransferase; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D015513:Oncogene Proteins / Q000378:metabolism*; D017368:Protein Prenylation / Q000187:drug effects*; D014166:Transferases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D009842:Oligopeptides; D015513:Oncogene Proteins; D014166:Transferases; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase