title: Disruption of oncogenic K-Ras4B processing and signaling by a potent geranylgeranyltransferase I inhibitor.
abstract: Prenylation of the carboxyl-terminal CAAX (C, cysteine; A, aliphatic acid; and X, any amino acid) of Ras is required for its biological activity. We have designed a CAAX peptidomimetic, GGTI-287, which is 10 times more potent toward inhibiting geranylgeranyltransferase I (GGTase I) in vitro (IC50 = 5 nM) than our previously reported farnesyltransferase inhibitor, FTI-276. In whole cells, the methyl ester derivative of GGTI-287, GGTI-286, was 25-fold more potent (IC50 = 2 microM) than the corresponding methyl ester of FTI-276, FTI-277, toward inhibiting the processing of the geranylgeranylated protein Rap1A. Furthermore, GGTI-286 is highly selective for geranylgeranylation over farnesylation since it inhibited the processing of farnesylated H-Ras only at much higher concentrations (IC50 > 30 microM). While the processing of H-Ras was very sensitive to inhibition by FTI-277 (IC50 = 100 nM), that of K-Ras4B was highly resistant (IC50 = 10 microM). In contrast, we found the processing of K-Ras4B to be much more sensitive to GGTI-286 (IC50 = 2 microM). Furthermore, oncogenic K-Ras4B stimulation inhibited potently by GGTI-286 (IC50 = 1 microM) but weakly by FTI-277 (IC50 = 30 microM). Significant inhibition of oncogenic K-Ras4B stimulation of MAP kinase by GGTI-286 occurred at concentrations (1-3 microM) that did not inhibit oncogenic H-Ras stimulation of MAP kinase. The data presented in this study provide the first demonstration of selective disruption of oncogenic K-Ras4B processing and signaling by a CAAX peptidomimetic. The higher sensitivity of K-Ras4B toward a GGTase I inhibitor has a tremendous impact on future research directions targeting Ras in anticancer therapy.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Pittsburgh, Pennsylvania 15261, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: Lerner
authors.forename: Y
authors.initials: Y
authors.lastname: Qian
authors.forename: A D
authors.initials: AD
authors.lastname: Hamilton
authors.forename: S M
authors.initials: SM
authors.lastname: Sebti
mesh_terms: D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D017368:Protein Prenylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014166:Transferases / Q000037:antagonists & inhibitors*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; C096855:GGTI 287; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018631:ras Proteins; D007930:Leucine