Farnesyltransferase (FTase) is a zinc enzyme that has been the subject of particular attention in anti-cancer research. Inhibitors of farnesyltransferase (FTase) have been designed for use as anti-Ras and anti-cancer drugs, but in fact they are selective for FTase, not for Ras. The non-thiol-containing FTI-2148 is highly selective for FTase (IC50, 1.4 nM) over GGTase I (IC50, 1700 nM). In whole cells, the corresponding methylester prodrug FTI-2153 is 3000-fold more potent at inhibiting H-Ras (IC50, 10 nM) than Rap1A processing. Furthermore, FTI-2153 is highly effective at suppressing oncogenic H-Ras constitutive activation of mitogen-activated protein kinase and human tumor growth in soft agar.

The FTase inhibitor FTI-2153 inhibits H-Ras processing with an IC50 of 10 nM. Thus, FTI-2153 is 10-fold more potent than FTI-277 at suppressing oncogenic H-Ras activation of MAPK. FTI-2153 inhibits the growth of the plastic of H-Ras-transformed NIH 3T3 cells and their parental cells. The IC50s are 0.3 and 10 μM, respectively. Furthermore, FTI-2153 at 30 μM results in 40% cell death of H-Ras-transformed NIH 3T3 cells and only 7% of NIH 3T3 cells. FTI-2153 also induces the accumulation of two human lung cancer cell lines in mitosis. Furthermore, FTI-2153 inhibits bipolar spindle formation during prometaphase.

FTI-2153 inhibits bipolar spindle formation and induces a rosette morphology with a monopolar spindle surrounded by chromosomes. The effect is in normal primary foreskin fibroblasts (HFF), human ovarian (OVCAR3), lung (A-549 and Calu-1) and fibrosarcoma (HT1080). All in all, FTI-2153 is a highly potent antagonist of FTase and oncogenic H-Ras signaling.

Sun J, et al. Antitumor efficacy of a novel class of non-thiol-containing peptidomimetic inhibitors of farnesyltransferase and geranylgeranyltransferase I: combination therapy with the cytotoxic agents cisplatin, Taxol, and gemcitabine. Cancer Res. 1999 Oct 1;59(19):4919-26.