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

Yimin Qian, Andreas Vogt, Saïd M. Sebti, Andrew D. Hamilton

Research output: Contribution to journalArticlepeer-review


Cysteine farnesylation of the ras oncogene product Ras is required for its transforming activity and is catalyzed by farnesyltransferase (FTase). The Ras 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 Ras CAAX non-peptide mimetics in which the cysteine is linked through a reduced pseudopeptide bond to 4-amino-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.

Original languageEnglish (US)
Pages (from-to)217-223
Number of pages7
JournalJournal of Medicinal Chemistry
Issue number1
StatePublished - Jan 5 1996

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


Dive into the research topics of 'Design and synthesis of non-peptide Ras CAAX mimetics as potent farnesyltransferase inhibitors'. Together they form a unique fingerprint.

Cite this