Non-peptidic prenyltransferase inhibitors: Diverse structural classes and surprising anti-cancer mechanisms

The development of farnesyltransferase. inhibitors (FTIs) has been one of t he 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 histo rical survey of the protein prenylation field is given, in particular to em phasize 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 dr ug target - farnesyltransferase (FTase). Numerous potent farnesyltransferas e inhibitors have been developed. The FTIs developed can be separated into three different categories, based on their origin and/or mechanism of actio n: a) natural products; b) peptidomimetics and other CAAX-competitive inhib itors; c) farnesyl pyrophosphate (FPP) mimetics or analogs and other FPP-co mpetitive inhibitors. Along with a survey of newer FTIs in each class, the development of several representative, potent compounds will be discussed i n depth as we discuss the potential advantages and liabilities of each clas s. Particular emphasis is given to the discovery of new, more potent FPP-co mpetitive 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 betw een these compounds and traditional cytotoxic cancer chemotherapeutic agent s, with surprising exceptions to their expected modes of action. As some FT Is have entered human clinical trials, answers may soon become available to key mechanistic questions concerning the, extent and nature of their antit umor growth properties.