Design and synthesis of non-peptide Ras CAAX mimetics as potent farnesyltransferase inhibitors

Cysteine farnesylation of the ras oncogene product Ras is required for its transforming activity and is catalyzed by farnesyltransferase (FTase). The Pas 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 Pas CAAX non-peptide mimetics in which the cysteine is Linked through a reduced pseudopeptide bond to kamino-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.