Current progress on farnesyl protein transferase inhibitors.

The hypothesis that the inhibition of farnesyl protein transferase (FPTase) may be beneficial in the treatment of certain cancers is finally being clinically tested. The efforts of almost a decade of preclinical research have resulted in several new chemical entities that are currently undergoing phase I, II or III clinical trials. The number of compounds being tested is small and disproportionate given the amount of effort by a large number of organizations in targeting FPTase. The three compounds, BMS-214662 (Bristol-Myers Squibb), R-115777 (Janssen Pharmaceutica BV) and Sch-66336 (Schering-Plough Research Institute) are the most advanced. While initial results with these three candidate drugs are encouraging, it is disappointing that the clinical efficacy of many other candidates has been less successful. In this review, we summarize the clinical and preclinical data published in 2001, and discuss the natural product inhibitors reported between 1998 to 2001. In addition, a comprehensive history of the FPTase inhibitory discovery effort at Merck, from CAAX tetrapeptides to peptidomimetics to macrocyclic compounds, is summarized for the first time.