Design and in vivo analysis of potent non-thiol inhibitors of farnesyl protein transferase

Inhibitors of farnesyl protein transferase (FPTase) based upon a pseudotrip eptide template are described that comprise an imidazole group substituted with a hydrophobic substituent. (1,5)-Disubstitution of the imidazole group is shown to be the optimal array that leads to potent and selective inhibi tors of FPTase. A variety of aryl and isoprenyl substituents are shown to a fford effective inhibitors, and the mechanism by which these compounds inhi bit FPTase has been investigated. The biochemical. behavior of these compou nds suggests that they bind to FPTase at the site usually occupied by the p rotein substrate. In experiments in cell culture, the methyl ester prodrugs of these inhibitors are cell permeant and potently inhibit the posttransla tional modification of H-Ras protein. Additionally, these molecules revert the phenotype of ras transformed cells as evidenced by their ability to slo w the growth of ras transformed cell lines in soft agar. One of the inhibit ors, as its methyl prodrug, was evaluated in two in vivo models of tumor gr owth. The compound selectively inhibited the growth of tumors derived from H-ras transformed cells, in nude mice, and caused the regression of preexis ting tumors in an H-ras transgenic animal model.