Farnesyltransferase Inhibitors as Anticancer Agents

Abstract

The long awaited molecular age of cancer diagnostics and pharmaceuticals is arriving at last, and it is fitting that drugs designed to interfere in the function of Ras, the first oncogenic protein found in human tumors, are leading the way. One class of such drugs, farnesyltransferase inhibitors (FTIs), illustrate both the promise and the cautions that accompany such molecularly targeted therapies. On one hand, FTIs represent a class of rationally designed drugs targeting the farnesyltransferase (FTase) enzyme that posttranslationally modifes Ras and other farnesylated proteins, and they have shown some efficacy in clinical trials as anticancer agents. On the other hand, several surprises have accompanied the development of FTIs, the most important of which is that FTIs do not inhibit Ras function primarily; indeed, the ultimate downstream targets of FTase inhibition are yet to be identified. This review describes the development of FTIs as anti-Ras and anticancer treatments, from both a basic and a translational science perspective, ending with a discussion of present understanding and future prospects for this novel class of therapeutic agents.