STRUCTURE-ACTIVITY-RELATIONSHIPS OF CYSTEINE-LACKING PENTAPEPTIDE DERIVATIVES THAT INHIBIT RAS FARNESYLTRANSFERASE

Mutational activation of ras has been found in many types of human can cers, including a greater than 50% incidence in colon and about 90% in pancreatic carcinomas. The activity of both native and oncogenic ras proteins requires a series of post-translational processing steps. The first event in this process is the farnesylation of a cysteine residu e located in the fourth position from the carboxyl terminus of the ras protein, catalyzed by the enzyme farnesyltransferase (FTase). Inhibit ors of FTase are potential candidates for development as antitumor age nts. Through a high-volume screening program, the pentapeptide derivat ive PD083176 (1), Cbz-His-Tyr(OBn)-Ser(OBn)-Trp-DAla-NH2, was identifi ed as an inhibitor of rat brain FTase, with an IC50 of 20 nM. Structur e-activity relationships were carried out to determine the importance of the side chain and chirality of each residue. This investigation le d to a series of potent FTase inhibitors which lack a cysteine residue as found in the ras peptide substrate. The parent compound (1) inhibi ted the insulin-induced maturation of Xenopus oocytes (concentration: 5 pmol/oocyte), a process which is dependent on the activation of the ras pathway.