Farnesyltransferase inhibitors:a cell signalling approach to the design of efficacious anticancer agents

Abstract

The emergence of farnesyltransferase (FTase) as an intensely investigated target for anticancer drug development was largely based on the potential of FTase inhibitors to effectively retard the growth of ras transformed tumours. Indeed, it has been well-established that Ras is readily prenylated by FTase and that inhibition of this reaction has functional consequences for the transformed phenotype of cells that express oncogenic Ras. Therefore, it has been envisioned that FTase inhibitors could potentially fulfil the huge therapeutic need existing for drugs that will effectively control the growth of colon and pancreatic tumours. While the prevalence of ras mutations is generally in the range of 30% across tumour types, colon and pancreatic cancers harbour ras mutations at a particularly high rate (50 and 90%, respectively). The medical need has not diminished since farnesyltransferase emerged onto the drug development scene. However, we now know that FTase inhibitors may well have significantly broader therapeutic activity than that first predicted. The ability of FTase inhibitors to effectively slow the growth of tumours that do not express oncogenic Ras has been an agreeable surprise. Indeed, the existence of multiple protein substrates for FTase should serve as a reminder that the true target under consideration is not Ras, but rather farnesyltransferase. Compounds from this therapeutic class are just beginning to enter the clinical arena. Thus, many years of preclinical investigation into the therapeutic potential of farnesyltransferase is now being put to the ultimate test. During the next two or three years, we are likely to get an answer to the question of whether this approach to signalling intervention will result in FTase inhibitors truly representing a new generation of anticancer drugs.