ras oncogenes are present in several types of cancers but are most frequently described in colon and pancreatic carcinomas. Consequently, ras is being targeted for drug development as a means to develop therapies for these types of cancer. The ras protein is posttranslationally modified by the addition of a farnesyl group, followed by cleavage of the COOH-terminal 3 amino acids and methylation of the prenylated cysteine. Because the posttranslational addition of farnesyl is obligatory not only for the remaining modifications to take place but also for ras control of cell growth, inhibitors of farnesylation are being developed as potential antitumor agents. In this report, a new peptidomimetic inhibitor of farnesyl transferase is described. This compound, B956, and its methyl ester B1086, inhibit the formation of colonies in soft agar of 14 human tumor cell lines expressing different ras oncogenes at concentrations between 0.2 and 60 µm. Higher concentrations of B956 (10–80 µm) were required to inhibit colony formation by 5 tumor cell lines without ras mutations. B956/B1086 at 100 mg/kg also inhibited tumor growth by EJ-1 human bladder carcinoma, HT1080 human fibrosarcoma, and to a lesser extent by HCT116 human colon carcinoma xenografts in nude mice. Furthermore, inhibition of tumor growth by B956 is shown to be correlated with inhibition of ras posttranslational processing in the tumor. Thus, peptidomimetic inhibitors of ras farnesylation have the potential to be developed as therapy for ras-dependent tumors.

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