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Leonard, D.M. et al.

Leonard, Shuler, Poulter, Eaton, Sawyer, Hodges, Su, Scholten, Gowan, Sebolt-Leopold, Doherty,

Structure-activity relationships of cysteine-lacking pentapeptide derivatives that inhibit ras farnesyltransferase.

Mutational activation of ras has been found in many types of human cancers, 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 residue located in the fourth position from the carboxyl terminus of the ras protein, catalyzed by the enzyme farnesyltransferase ( FTase). Inhibitors of FTase are potential candidates for development as antitumor agents. Through a high-volume screening program, the pentapeptide derivative PD083176 (1), Cbz-His-Tyr(OBn)-Ser(OBn)-Trp-DAla-NH2, was identified as an inhibitor of rat brain FTase, with an IC50 of 20 nM. Structure-activity relationships were carried out to determine the importance of the side chain and chirality of each residue. This investigation led to a series of potent FTase inhibitors which lack a cysteine residue as found in the ras peptide substrate. The parent compound (1) inhibited the insulin-induced maturation of Xenopus oocytes (concentration: 5 pmol/oocyte), a process which is dependent on the activation of the ras pathway.[1]

References

Structure-activity relationships of cysteine-lacking pentapeptide derivatives that inhibit ras farnesyltransferase. Leonard, D.M., Shuler, K.R., Poulter, C.J., Eaton, S.R., Sawyer, T.K., Hodges, J.C., Su, T.Z., Scholten, J.D., Gowan, R.C., Sebolt-Leopold, J.S., Doherty, A.M. J. Med. Chem. (1997) [Pubmed]

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