Antitumor activity of ER-51785, a new peptidomimetic inhibitor of farnesyl transferase: synergistic effect in combination with paclitaxel.

Inhibitors of ras farnesylation have been extensively studied in the preclinical stage, and some of them are being developed in the clinic. Herein, we describe the antitumor activity of a new farnesyl transferase inhibitor, ER-51785. In vitro, ER-51785 selectively inhibited farnesyl transferase activity (IC 50 = 77 nM) compared with geranylgeranyl transferase I activity (IC 50 = 4200 nM). In cells, ER-51785 inhibited posttranslational processing of H-ras with IC 50 = 28 nM, but not that of rap 1A at concentrations up to 50 μM. This compound also strongly inhibited colony formation of H-ras-transformed NIH 3T3 fibroblasts and EJ- bladder carcinoma cells. In vivo, ER-51785 showed potent tumor regression activity against EJ-1 xenografts but only modest activity against MIA PaCa-2 xenografts. Treatment of ER-51785 in combination with paclitaxel exhibited synergistic effects against colony formation and tumor growth of MIA PaCa-2 cells. The results presented herein support the idea that farnesyl transferase inhibitors alone and in combination with other chemotherapeutic agents have the potential to be developed as therapies for tumors expressing H-ras or K-ras oncogenes.