Probing the hydrophobic pocket of farnesyltransferase: Aromatic substitution of CAAX peptidomimetics leads to highly potent inhibitors

Cysteine farnesylation at the carboxylate terminal tetrapeptide CAAX of Ras protein is catalyzed by farnesyltransferase. This lipid modification is ne cessary for regulatory function of both normal and oncogenic Ras. The high frequency of Ras mutation in human cancers has prompted an intensive study on finding ways of controlling oncogenic Ras function. Inhibition of farnes yltransferase is among the most sought after targets for cancer chemotherap y. We report here the design, synthesis and biological characterization of a series of peptidomimetics as farnesyltransferase inhibitors. These compou nds are extremely potent towards farnesyltransferase with IC50 values rangi ng from subnanomolar to low nanomolar concentrations. They have a high sele ctivity for farnesyltransferase over the closely related geranylgeranyltran sferase-I. Structure-activity relationship studies demonstrated that a prop erly positioned hydrophobic group significantly enhanced inhibition potency , reflecting an improved complementarity to the large hydrophobic pocket in the CAAX binding site. (C) 1999 Elsevier Science Ltd. All rights reserved.