title: Potent, cell active, non-thiol tetrapeptide inhibitors of farnesyltransferase.
abstract: All previously reported CAAX-based farnesyltransferase inhibitors contain a thiol functionality. We report that attachment of the 4-imidazolyl group, via 1-, 2-, or 3-carbon alkyl or alkanoyl spacers, to Val-Tic-Met or tLeu-Tic-Gln provides potent FT inhibitors. (R*)-N-[[1,2,3,4-Tetrahydro-2-[N-[2-(1H-imidazol-4-yl)ethyl] -L-valyl]-3-isoquinolinyl]carbonyl]-L-methionine ([imidazol- 4-yl-ethyl]-Val-Tic-Met), with FT IC50 = 0.79 nM, displayed potent cell activity in the absence of prodrug formation (SAG EC50 = 3.8 muM).
authors.affiliation: Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Hunt
authors.forename: V G
authors.initials: VG
authors.lastname: Lee
authors.forename: K
authors.initials: K
authors.lastname: Leftheris
authors.forename: B
authors.initials: B
authors.lastname: Seizinger
authors.forename: J
authors.initials: J
authors.lastname: Carboni
authors.forename: J
authors.initials: J
authors.lastname: Mabus
authors.forename: C
authors.initials: C
authors.lastname: Ricca
authors.forename: N
authors.initials: N
authors.lastname: Yan
authors.forename: V
authors.initials: V
authors.lastname: Manne
mesh_terms: D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases; D000595:Amino Acid Sequence; D000818:Animals; D051231:Farnesyltranstransferase; D051379:Mice; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D014166:Transferases / Q000037:antagonists & inhibitors*
chemical_list: D009842:Oligopeptides; D014166:Transferases; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase