The development of
farnesyltransferase inhibitors (FTIs) has been one of the most active areas of anticancer
drug development for the past ten years. This review presents a general overview of the developments in this area, along with a critical appraisal of the anticancer activity of FTIs. A historical survey of the protein prenylation field is given, in particular to emphasize the key role played by the Ras
oncoprotein in driving the discovery of
prenyltransferase enzymes. The different classes of prenylated
proteins will be described along with the biochemical characteristics of the key
drug target--
farnesyltransferase (FTase). Numerous potent
farnesyltransferase inhibitors have been developed. The FTIs developed can be separated into three different categories, based on their origin and/or mechanism of action: a) natural products; b)
peptidomimetics and other CAAX-competitive inhibitors; c)
farnesyl pyrophosphate (FPP) mimetics or analogs and other FPP-competitive inhibitors. Along with a survey of newer FTIs in each class, the development of several representative, potent compounds will be discussed in depth as we discuss the potential advantages and liabilities of each class. Particular emphasis is given to the discovery of new, more potent FPP-competitive FTIs of several diverse structural classes. Testing of different FTIs for their ability to block the growth of various
cancer cell types in animal models will be discussed. There are a number of key differences between these compounds and traditional cytotoxic
cancer chemotherapeutic agents, with surprising exceptions to their expected modes of action. As some FTIs have entered human clinical trials, answers may soon become available to key mechanistic questions concerning the extent and nature of their antitumor growth properties.