L-778,123

L-778,123 is a dual inhibitor of farnesyl transferase (FTase; IC₅₀ = 2 nM) and geranylgeranyl transferase type I (GGTase I; IC₅₀ = 98 nM).¹ It inhibits prenylation of the FTase and GGTase I substrates HDJ2 and Rap1a in PSN-1 pancreatic tumor cells (EC₅₀s = 92 and 6,760 nM, respectively). L-778,123 (1-300 μM) also inhibits prenylation of the oncogenic protein Ki-Ras in PSN-1 cells in a concentration-dependent manner. Ex vivo, L-778,123 (35-50 mg/kg per day) reduces HDJ2 and Rap1a prenylation in dog peripheral blood mononuclear cells (PBMCs) but has no effect on Ki-Ras prenylation in patient-derived PBMCs. L-778,123 inhibits lectin-induced expression of the T cell activation markers CD71 and CD25 on human PMBCs (IC₅₀s = 6.48 and 84.1 μM, respectively) and inhibits IL-2-induced proliferation of CTLL2 cells (IC₅₀ = 0.81 μM).²

1.Lobell, R.B., Liu, D., Buser, C.A., et al.Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-IMol. Cancer Ther.1(9)747-758(2002) 2.Si, M.-S., Reitz, B.A., and Borie, D.C.Inhibition of lymphocyte activation and function by the prenylation inhibitor L-778,123Invest New Drugs23(1)21-29(2005)