title: Design and synthesis of non-peptide Ras CAAX mimetics as potent farnesyltransferase inhibitors.
abstract: Cysteine farnesylation of the ras oncogene product Ras is required for its transforming activity and is catalyzed by farnesyltransferase (FTase). The Ras carboxyl terminal tetrapeptide CAAX (C is cysteine, A is any aliphatic amino acid, X is methionine or serine) is the minimum sequence for FTase recognition. We report here the design, synthesis, and biological characterization of Ras CAAX non-peptide mimetics in which the cysteine is linked through a reduced pseudopeptide bond to 4-amino-3'-carboxybiphenyl. These non-peptide mimetics are potent inhibitors of FTase (IC50 = 40 nM for the most potent inhibitor) and are highly selective for FTase over GGTase I (geranylgeranyltransferase I). They are not substrates for farnesylation, do not have peptidic features, and have no hydrolyzable bonds. Structure-activity studies reveal the importance of the position of the carboxylic acid on the aryl ring as well as the reduction of the cysteine amide bond. Substitution at the 2-position of 4-amino-3'-carboxybiphenyl increases inhibitory potency, while the removal of the carboxylic acid results in a 10-fold loss of inhibitory activity.
authors.affiliation: Department of Chemistry, Faculty of Arts and Science, School of Medicine, University of Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Qian
authors.forename: A
authors.initials: A
authors.lastname: Vogt
authors.forename: S M
authors.initials: SM
authors.lastname: Sebti
authors.forename: A D
authors.initials: AD
authors.lastname: Hamilton
mesh_terms: D019883:Alkyl and Aryl Transferases; D000595:Amino Acid Sequence; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D017368:Protein Prenylation / Q000187:drug effects; D013329:Structure-Activity Relationship; D014166:Transferases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; C057785:S-farnesylcysteine; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase; D015689:Oncogene Protein p21(ras); D003545:Cysteine