Farnesyltransferase Inhibitors: Preclinical Development

Abstract

The Ras proteins are low molecular weight GTP binding proteins that function in the regulation of the transduction of growth proliferative signals from the membrane to the nucleus. Oncogenically mutated ras genes are found in approximately 25% of all human cancers. Localization of the Ras oncoproteins to the inner surface of the plasma membrane is essential for their biological activity. This observation suggested that the enzyme that mediates the membrane localization, farnesyl-protein transferase (FPTase), would be a target for the development of novel anticancer agents. We have developed potent, cell-active inhibitors of FPTase that exhibit antiproliferative activity in cell culture and block the morphologic alterations associated with Ras-induced transformation of mammalian cells in monolayer cultures. In vivo, these compounds block the growth of ras-transformed fibroblasts in a nude mouse xenograft model and block the growth and, in some cases, cause regression of mammary and salivary tumors in several strains of ras transgenic mice in the absence of any detectable side effects. The results of our preclinical studies and those of others suggest that FTIs may have utility against a variety of human cancers, a hypothesis that is currently being tested in the clinic.

Inhibition of farnesyltransferase increases TGFβ type II receptor expression and enhances the responsiveness of human cancer cells to TGFβ

“…Several small GTPases such as H-Ras, N-Ras, KRas and RhoB, are modi®ed by farnesylation. Inhibition of farnesylation by FTIs was shown to inhibit the growth of Ras-and non Ras-transformed cells and lead to complete tumor regression in mice expressing oncogenic transgenes (Kohl, 1999;Lebowitz and Prendergast, 1998;Norgaard et al, 1999;Oli , 1999;Rowinsky et al, 1999;Sebti and Hamilton, 1997). To determine whether FTIs could a ect TGFb function, we analysed the growth of human pancreatic carcinoma cells, Panc-1, which are weakly sensitive to TGFb, in response to FTI-277 and TGFb.…”

Short-Term Local Delivery of an Inhibitor of Ras Farnesyltransferase Prevents Neointima Formation In Vivo After Porcine Coronary Balloon Angioplasty

“…Furthermore, FTase also catalyzes Rho farnesylation, another small-molecular-mass G protein involved in a separate pathway that plays a significant role in regulating cell proliferation. Inhibitors of FTase have been under development for applications in cancer therapy for several years 7 because of their ability to prevent excessive cell growth in cancer cell lines. Inhibitors of FTase can also inhibit proliferation 8,9 and migration 8 of vascular SMCs in vitro.…”

Exploring Structure-Activity Relationships of Tricyclic Farnesyltransferase Inhibitors Using ECLiPS® Libraries

“…Although representatives of all these classes of compounds are capable of inhibiting the growth of both transformed cell lines and tumors in nude mice, efficacy does not always correlate with Ras activation status [12]. This finding indicates that farnesylated proteins, in addition to Ras, are involved in cancer.…”