PSEUDOPEPTIDE INHIBITORS OF RAS FARNESYL-PROTEIN TRANSFERASE

Inhibitors of Ras farnesyl-protein transferase are described. These ar e reduced pseudopeptides related to the C-terminal tetrapeptide of the Ras protein that signals farnesylation. Deletion of the carbonyl grou ps between the first two residues of the tetrapeptides either preserve s or improves activity, depending on the peptide sequence. The most po tent in vitro enzyme inhibitor described (IC50 = 5 nM) is Cys[PSICH2NH ]Ile[PSICH2NH]Phe-Met(3). To obtain compounds able to suppress Ras far nesylation in cell culture, further structural modification to include a homoserine lactone prodrug was required. Compound 18(Cys[PSICH2NH]I le[PSICH2NH]Ile-homoserine lactone)reduced the extent of Ras farnesyla tion by 50 % in NIH3T3 fibroblasts in culture at a concentration of 50 muM. Structure-activity studies also led to 12 (Cys[PSICH2NH]Val-Ile- Leu), a potent and selective inhibitor of a related enzyme, the type-I geranylgeranyl protein transferase.