Selective Inhibition of ras -Dependent Transformation by a Farnesyltransferase Inhibitor

Abstract

To acquire transforming potential, the precursor of the Ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase (FPTase), have therefore been suggested as anticancer agents for tumors in which Ras contributes to transformation. The tetrapeptide analog L-731,735 is a potent and selective inhibitor of FPTase in vitro. A prodrug of this compound, L-731,734, inhibited Ras processing in cells transformed with v-ras. L-731,734 decreased the ability of v-ras-transformed cells to form colonies in soft agar but had no effect on the efficiency of colony formation of cells transformed by either the v-raf or v-mos oncogenes. The results demonstrate selective inhibition of ras-dependent cell transformation with a synthetic organic inhibitor of FPTase.

Modeling human lung cancer in mice: similarities and shortcomings

“…For example, loci that modify lung cancer susceptibility, such as K-ras, would be appropriate targets to examine in susceptible mice by treating them with FPT inhibitors (Kohl et al, 1993).…”

Both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for inhibition of oncogenic K-Ras prenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts

“…Because farnesylation is su cient and required for membrane anchoring of Ras and malignant transformation (Kato et al, 1992), FTase has become one of the most sought-after targets for developing novel anticancer drugs Satler and Tamanoi, 1996;Buss and Marsters, 1995;Gibbs et al, 1994). Over the last 5 years we Nigam et al, 1993;Qian et al, 1994a, b;Vogt et al, 1995) and others (Kohl et al, 1993;James et al, 1993;Graham et al, 1994;Patel et al, 1995;Bishop et al, 1995;Garcia et al, 1993) have used the CAAX tetrapeptide to design peptidomimetics that are highly selective and potent inhibitors of FTase. These inhibitors disrupted oncogenic H-Ras but not Raf signaling and inhibited tumor growth in nude mice of NIH3T3 cells transformed by H-ras but not those transformed by Raf oncogenes (Sun et al, l995;Kohl et al, 1995;Nagasu et al, 1995).…”

“…These inhibitors disrupted oncogenic H-Ras but not Raf signaling and inhibited tumor growth in nude mice of NIH3T3 cells transformed by H-ras but not those transformed by Raf oncogenes (Sun et al, l995;Kohl et al, 1995;Nagasu et al, 1995). Furthermore, CAAX peptidomimetics inhibited the anchorage-dependent growth of ras-transformed cells but had little e ect on the growth of normal cells (Kohl et al, 1993;James et al, 1993). However, the ability of FTase inhibitors to reverse morphological transformation was shown not to correlate with their ability to inhibit Ras prenylation (Prendergast et al, 1994), and the Ras mutation status did not predict the sensitivity of human tumor cell growth in soft agar (SeppLorenzino et al, 1995).…”

New agents in acute myeloid leukemia and other myeloid disorders

“…Several pharmacologic inhibitors of Ftase have been developed. 67 Four such Ftase inhibitors are in clinical trials: R115777 (Zarnestra), SCH66336, L778123, and BMS214662. 68 -70 These agents may have Ras independent effects on other cellular signaling components that may contribute to their antileukemic action.…”