ADVANCES IN THE DEVELOPMENT OF FARNESYLTRANSFERASE INHIBITORS - SUBSTRATE RECOGNITION BY PROTEIN FARNESYLTRANSFERASE

A variety of compounds that show promise in cancer chemotherapy and ch emoprevention have been identified as farnesyltransferase inhibitors. These can be classified into mainly two different types of inhibitors, farnesyl diphosphate competitors and CAAX peptidomimetics. The former type acts by competitively inhibiting farnesyltransferase with respec t to one of the substrates, farnesyl diphosphate, whereas the latter t ype acts by mimicking the other substrate, the C-terminal CAAX motif o f Ras protein. One example of a farnesyl diphosphate competitor is man umycin, an antibiotic detected in the culture media of a Streptomyces strain. The CAAX peptidomimetics were developed based on the unique pr operty of farnesyltransferase to recognize the CAAX motif at the C-ter minus of the protein substrate. Our recent studies have focused on und erstanding the structural basis of this CAAX recognition. By using in vitro mutagenesis, residues of yeast farnesyltransferase important for the recognition of the CAAX motif have been identified. Two of these residues are closely located at the C-terminal region of the beta-subu nit of farnesyltransferase. These and other results on the structural basis of the CAAX recognition may provide information valuable for str ucture-based design of farnesyltransferase inhibitors. (C) 1998 Wiley- Liss, Inc.dagger