title: From peptide libraries to optimized nonpeptide ligands in the search for S-farnesyltransferase inhibitors.
abstract: A complete 331,776-member library of tetrapeptides made of 24 amino acid building blocks was synthesized robotically on solid phase and subjected to a deconvolution based on the inhibitory potency of the sublibraries in a HPLC assay of the S-farnesyltransferase activity in vitro. One of the non-natural peptide and noncysteine-containing leads Nip-Trp-Phe-His (Nip=p-nitrophenyl-L-alanine) was optimized chemically to give a proteolytically stable pseudopeptide with a 200-fold potency compared with the original lead. The final compound was converted to the C-terminal ethyl ester: p-F-C6H4-CO(CH2)2-CO-Bta-D-Phepsi[CH2NH]His-OEt (Bta = benzothienyl-L-alanine) and shown to behave as a prodrug which was hydrolyzed back to the C-terminal acid following cell penetration. The method confirmed that several structurally original leads can be discovered in large libraries when deconvolution relies upon a highly specific assay and that these leads can be optimized by chemical modification to impart the final compound the desired pharmacological and pharmacokinetic properties.
authors.affiliation: Institut de Recherches Servier, Suresnes, France.
authors.forename: J M
authors.initials: JM
authors.lastname: Henlin
authors.forename: J A
authors.initials: JA
authors.lastname: Boutin
authors.forename: N
authors.initials: N
authors.lastname: Kucharczyk
authors.forename: C
authors.initials: C
authors.lastname: Desmet-Beaufort
authors.forename: A
authors.initials: A
authors.lastname: Loynel
authors.forename: M
authors.initials: M
authors.lastname: Bertrand
authors.forename: A
authors.initials: A
authors.lastname: Genton
authors.forename: G C
authors.initials: GC
authors.lastname: Tucker
authors.forename: G
authors.initials: G
authors.lastname: Atassi
authors.forename: J L
authors.initials: JL
authors.lastname: Fauchére
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D008024:Ligands; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase