Oncogenic Ras proteins transform animal cells to a malignantphenotype only when modified by farnesyl residues attached tocysteines near their carboxyl termini. The farnesyltransferase thatcatalyzes this reaction recognizes tetrapeptides of the sequence CAAX,where C is cysteine, A is an aliphatic amino acid, and X is acarboxyl-terminal methionine or serine. Replacement of the twoaliphatic residues with a benzodiazepine-based mimic of a peptide turngenerated potent inhibitors of farnesyltransferase [50 percentinhibitory concentration (IC50) < 1 nM]. Unlike tetrapeptides, thebenzodiazepine peptidomimetics enter cells and block attachment offarnesyl to Ras, nuclear lamins, and several other proteins. Atmicromolar concentrations, these inhibitors restored a normal growthpattern to Ras-transformed cells. The benzodiazepine peptidomimeticsmay be useful in the design of treatments for tumors in whichoncogenic Ras proteins contribute to abnormal growth, such as that ofthe colon, lung, and pancreas.