4 Farnesyltransferase inhibitors

Publisher Summary The farnesyltransferase inhibitors (FTIs) have been developed to the point that the fundamental hypotheses generated in preclinical studies can be directly tested in people. Since the time when efforts to develop inhibitors of farnesyltransferase (FTase) for cancer began, two fundamental pieces of information have been learned. First, the number of proteins known to be farnesylated is much larger than originally recognized, with at least 20 proteins identified so far. Some of these proteins may contribute to the biology of FTIs. Second, the cross-prenylation of N-Ras and Ki-Ras proteins by geranylgeranyltransferase type I (GGTase-I) in cells treated with FTIs showed that inhibiting the function of these forms of Ras that are most closely associated with the clinical disease in humans, is more complicated than originally envisioned. Nevertheless, the efficacy of FTIs in the preclinical models warranted evaluation in the clinic. Given that FTIs can no longer be viewed as the laser beam therapy for Ras-mediated malignancy, it is not surprising that the dose-limiting toxicities noted in the phase I clinical trials are similar to those found with currently used antiproliferative drugs.