title: Potent and selective farnesyl transferase inhibitors.
abstract: We recently described a novel series of CA(1)A(2)X peptidomimetics as farnesyl transferase inhibitors (FTIs). These compounds possess an N-(4-piperidinyl)benzamide scaffold mimicking A(1)A(2) residue. Extensive exploration of structure--activity relationships revealed that replacement of cysteine by substituted benzylimidazoles provided nanomolar FTIs with in vitro activities (18e, IC(50) = 4.60 nM on isolated enzyme, EC(50) = 20.0 nM for growth inhibition on a tumor cell line). The molecular docking of 18e and 19e in the active site of the enzyme provided details of key interactions with the protein and showed that the methionine or phenylalanine residue fits into the aryl binding site.
authors.affiliation: Institut de Chimie Pharmaceutique Albert Lespagnol, EA 2692, Université de Lille 2, BP 83 rue du Professeur Laguesse, 59006 Lille, France.
authors.forename: Régis
authors.initials: R
authors.lastname: Millet
authors.forename: Juozas
authors.initials: J
authors.lastname: Domarkas
authors.forename: Raymond
authors.initials: R
authors.lastname: Houssin
authors.forename: Pauline
authors.initials: P
authors.lastname: Gilleron
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Goossens
authors.forename: Philippe
authors.initials: P
authors.lastname: Chavatte
authors.forename: Cédric
authors.initials: C
authors.lastname: Logé
authors.forename: Nicole
authors.initials: N
authors.lastname: Pommery
authors.forename: Jean
authors.initials: J
authors.lastname: Pommery
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hénichart
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051231:Farnesyltranstransferase; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase