BENZODIAZEPINE PEPTIDOMIMETICS - POTENT INHIBITORS OF RAS FARNESYLATION IN ANIMAL-CELLS

Oncogenic Ras proteins transform animal cells to a malignant phenotype only when modified by farnesyl residues attached to cysteines near th eir carboxyl termini. The farnesyltransferase that catalyzes this reac tion recognizes tetrapeptides of the sequence CAAX, where C is cystein e, A is an aliphatic amino acid, and X is a carboxyl-terminal methioni ne or serine. Replacement of the two aliphatic residues with a benzodi azepine-based mimic of a peptide turn generated potent inhibitors of f arnesyltransferase [50 percent inhibitory concentration (IC50) < 1 nM] . Unlike tetrapeptides, the benzodiazepine peptidomimetics enter cells and block attachment of farnesyl to Ras, nuclear lamins, and several other proteins. At micromolar concentrations, these inhibitors restore d a normal growth pattern to Ras-transformed cells. The benzodiazepine peptidomimetics may be useful in the design of treatments for tumors in which oncogenic Ras proteins contribute to abnormal growth, such as that of the colon, lung, and pancreas.