Showing papers by "Jackson B. Gibbs published in 1999"
TL;DR: Investigation of farnesyltransferase inhibitor L-744,832 in an in vivo murine model of myeloid leukemia that is associated with inactivation of the Nf1 tumor suppressor gene finds that the lack of efficacy in this model is due to the resistance of N-Ras and K-Ra processing to inhibition by this FTI.
78 citations
TL;DR: The design and syntheses of non-thiol inhibitors of farnesyl-protein transferase are described, which led to highly potent imidazole-containing diarylethers and diarylsulfones and Polar diaryl linkers dramatically improved potency and gave highly cell active compounds.
64 citations
TL;DR: Inhibitors of farnesyl protein transferase (FPTase) based upon a pseudotripeptide template are described that comprise an imidazole group substituted with a hydrophobic substituent that selectively inhibited the growth of tumors derived from H-ras transformed cells, in nude mice, and caused the regression of preexisting tumors in an H-ra transgenic animal model.
Abstract: Inhibitors of farnesyl protein transferase (FPTase) based upon a pseudotripeptide 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 inhibitors of FPTase A variety of aryl and isoprenyl substituents are shown to afford effective inhibitors, and the mechanism by which these compounds inhibit FPTase has been investigated The biochemical behavior of these compounds suggests that they bind to FPTase at the site usually occupied by the protein substrate In experiments in cell culture, the methyl ester prodrugs of these inhibitors are cell permeant and potently inhibit the posttranslational modification of H-Ras protein Additionally, these molecules revert the phenotype of ras transformed cells as evidenced by their ability to slow the growth of ras transformed cell lines in soft agar One of the inhibitors, as its methyl prodrug, was evaluated in t
43 citations
TL;DR: The design and syntheses of non-thiol inhibitors of farnesyl-protein transferase are described and Substitutions on an imidazolylmethyl-AMBA-methionine template gave a highly potent and cell-active inhibitor.
28 citations