title: Benzodiazepine peptidomimetic inhibitors of farnesyltransferase.
abstract: A structural survey of protein Zn2+ binding geometries was instigated based upon the functional requirement of Ras farnesyltransferase for Zn2+. The Cys-X-X-Cys motif found in Zn(2+)-binding proteins such as aspartate transcarbamylase was used as a template to devise a bidentate-coordination model for Cys-A1-A2-X peptide inhibitors. Accordingly, replacement of the central dipeptide with the hydrophobic scaffold 3-amino-1-carboxymethyl-2,3-dihydro-5- phenyl-1H-1,4-benzodiazepin-2-one (BZA) yielded a peptidomimetic inhibitor, Cys(BZA)Met, of moderate potency (IC50 = 400 nM). N-Methylation of the cysteine amide improved potency almost 100-fold (IC50 = 0.3-1 nM). The increased affinity presumably correlates with a preferred conformation of the inhibitor which maximizes a hydrophobic interaction between the scaffold and the enzyme, and the proper presentation of cysteine and methionine to allow bidentate coordination at Zn2+. These non-peptide inhibitors have been shown to block farnesylation of the Ras protein in intact cells and provide lead compounds for the development of new cancer therapeutic agents.
authors.affiliation: Department of Bioorganic Chemistry, Genentech Inc., South San Francisco, CA 94080.
authors.forename: J C
authors.initials: JC
authors.lastname: Marsters
authors.forename: R S
authors.initials: RS
authors.lastname: McDowell
authors.forename: M E
authors.initials: ME
authors.lastname: Reynolds
authors.forename: D A
authors.initials: DA
authors.lastname: Oare
authors.forename: T C
authors.initials: TC
authors.lastname: Somers
authors.forename: M S
authors.initials: MS
authors.lastname: Stanley
authors.forename: T E
authors.initials: TE
authors.lastname: Rawson
authors.forename: M E
authors.initials: ME
authors.lastname: Struble
authors.forename: D J
authors.initials: DJ
authors.lastname: Burdick
authors.forename: K S
authors.initials: KS
authors.lastname: Chan
mesh_terms: D019883:Alkyl and Aryl Transferases; D000595:Amino Acid Sequence; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000494:pharmacology*; D002463:Cell Membrane Permeability; D051231:Farnesyltranstransferase; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014166:Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D009842:Oligopeptides; D001569:Benzodiazepines; D014166:Transferases; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase