Pseudopeptide inhibitors of Ras farnesyl-protein transferase

• Published in: Journal of medicinal chemistry Vol. 37; no. 6; pp. 725 - 732
• Main Authors: Graham, S L, deSolms, S J, Giuliani, E A, Kohl, N E, Mosser, S D, Oliff, A I, Pompliano, D L, Rands, E, Breslin, M J, Deana, A A
• Format: Journal Article
• Language: English
• Published: United States 18-03-1994
• Subjects: Alkyl and Aryl Transferases; Amino Acid Sequence; Animals; Cattle; Cells, Cultured; Dipeptides - chemical synthesis; Dipeptides - pharmacology; Farnesyltranstransferase; Molecular Sequence Data; Oligopeptides - chemical synthesis; Oligopeptides - pharmacology; Protein Prenylation - drug effects; Stereoisomerism; Structure-Activity Relationship; Transferases - antagonists & inhibitors
• ISSN: 0022-2623
• DOI: 10.1021/jm00032a004

Inhibitors of Ras farnesyl-protein transferase are described. These are reduced pseudopeptides related to the C-terminal tetrapeptide of the Ras protein that signals farnesylation. Deletion of the carbonyl groups between the first two residues of the tetrapeptides either preserves or improves activity, depending on the peptide sequence. The most potent in vitro enzyme inhibitor described (IC50 = 5 nM) is Cys [psi CH2NH]Ile[psi CH2NH]Phe-Met (3). To obtain compounds able to suppress Ras farnesylation in cell culture, further structural modification to include a homoserine lactone prodrug was required. Compound 18 (Cys[psi CH2NH]Ile[psi CH2NH]Ile-homoserine lactone) reduced the extent of Ras farnesylation by 50% in NIH3T3 fibroblasts in culture at a concentration of 50 microM. Structure-activity studies also led to 12 (Cys[psi CH2NH]Val-Ile-Leu), a potent and selective inhibitor of a related enzyme, the type-I geranylgeranyl protein transferase.