title: Inhibition of Ras prenylation: a signaling target for novel anti-cancer drug design.
abstract: The cancer-causing activity of Ras requires the prenylation of a cysteine fourth from its carboxyl terminus. Rational design of peptidomimetics of the carboxyl terminal tetrapeptide prenylation site on Ras resulted in pharmacological agents capable of inhibiting Ras processing, selectively antagonizing oncogenic signaling and suppressing human tumor growth in mouse models without side effects. This mini-review describes the efforts of several groups to design, synthesize and evaluate the biological activities of farnesyltransferase and geranylgeranyltransferase I inhibitors. Among the important issues that will be discussed are the mechanism of action of these inhibitors and the potential mechanisms of resistance to inhibition of K-Ras farnesylation.
authors.affiliation: H. Lee Moffitt Cancer Center, Department of Biochemistry and Molecular Biology, University of South Florida, Tampa 33612, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: Lerner
authors.forename: A D
authors.initials: AD
authors.lastname: Hamilton
authors.forename: S M
authors.initials: SM
authors.lastname: Sebti
mesh_terms: D019883:Alkyl and Aryl Transferases; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004122:Dimethylallyltranstransferase / Q000037:antagonists & inhibitors*; D015195:Drug Design; D051231:Farnesyltranstransferase; D006801:Humans; D051379:Mice; D017368:Protein Prenylation / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D014166:Transferases / Q000037:antagonists & inhibitors; D018631:ras Proteins / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D004122:Dimethylallyltranstransferase; D051231:Farnesyltranstransferase; D018631:ras Proteins