Farnesylation, the post-translational addition of a 15-carbon isoprenyl group, alters the function of several proteins, including Ras proteins. LB 42708 is a potent inhibitor of farnesyltransferase (FTase), blocking farnesylation of H-Ras, N-Ras, and K-Ras4B with IC50 values of 0.8, 1.2, and 2.0 nM, respectively. It displays over 50,000-fold selectivity for FTase over geranylgeranyltransferase I. LB 42708 prevents the farnesylation of H-Ras in response to LPS plus IFN-γ (IC50 = 10 nM), preventing activation of NF-κB as well as downstream signaling. These effects are obtained both in RAW 264.7 mouse macrophages and in mice. LB42708 also inhibits Ras-dependent signaling in endothelial cells, stopping VEGF-mediated angiogenesis both in vitro and in vivo.
