title: Probing the hydrophobic pocket of farnesyltransferase: aromatic substitution of CAAX peptidomimetics leads to highly potent inhibitors.
abstract: Cysteine farnesylation at the carboxylate terminal tetrapeptide CAAX of Ras protein is catalyzed by farnesyltransferase. This lipid modification is necessary for regulatory function of both normal and oncogenic Ras. The high frequency of Ras mutation in human cancers has prompted an intensive study on finding ways of controlling oncogenic Ras function. Inhibition of farnesyltransferase is among the most sought after targets for cancer chemotherapy. We report here the design, synthesis and biological characterization of a series of peptidomimetics as farnesyltransferase inhibitors. These compounds are extremely potent towards farnesyltransferase with IC50 values ranging from subnanomolar to low nanomolar concentrations. They have a high selectivity for farnesyltransferase over the closely related geranylgeranyltransferase-I. Structure-activity relationship studies demonstrated that a properly positioned hydrophobic group significantly enhanced inhibition potency, reflecting an improved complementarity to the large hydrophobic pocket in the CAAX binding site.
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06511, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Qian
authors.forename: J J
authors.initials: JJ
authors.lastname: Marugan
authors.forename: R D
authors.initials: RD
authors.lastname: Fossum
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 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001665:Binding Sites; D002460:Cell Line; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015335:Molecular Probes; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D015335:Molecular Probes; D009842:Oligopeptides; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; D018631:ras Proteins