title: Farnesyltransferase inhibitors and anti-Ras therapy.
abstract: The oncoprotein encoded by mutant ras genes is initially synthesized as a cytoplasmic precursor which requires posttranslational processing to attain biological activity; farnesylation of the cysteine residue present in the CaaX motif located at the carboxy-terminus of all Ras proteins is the critical modification. Once farnesylated and further modified, the mature Ras protein is inserted into the cell's plasma membrane where it participates in the signal transduction pathways that control cell growth and differentiation. The farnesylation reaction that modifies Ras and other cellular proteins having an appropriate CaaX motif is catalyzed by a housekeeping enzyme termed farnesyl-protein transferase (FPTase). Inhibitors of this enzyme have been prepared by several laboratories in an effort to identify compounds that would block Ras-induced cell transformation and thereby function as Ras-specific anticancer agents. A variety of natural products and synthetic organic compounds were found to block farnesylation of Ras proteins in vitro. Some of these compounds exhibit antiproliferative activity in cell culture, block the morphological alterations associated with Ras-transformation, and can block the growth of Ras-transformed cell lines in tumor colony-forming assays. By contrast, these compounds do not affect the growth or morphology of cells transformed by the Raf or Mos oncoproteins, which do not require farnesylation to achieve biological activity. The efficacy and lack of toxicity observed with FPTase inhibitors in an animal tumor model suggest that specific FPTase inhibitors may be useful for the treatment of some types of cancer.
authors.affiliation: Department of Cancer Research, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Gibbs
authors.forename: N E
authors.initials: NE
authors.lastname: Kohl
authors.forename: K S
authors.initials: KS
authors.lastname: Koblan
authors.forename: C A
authors.initials: CA
authors.lastname: Omer
authors.forename: L
authors.initials: L
authors.lastname: Sepp-Lorenzino
authors.forename: N
authors.initials: N
authors.lastname: Rosen
authors.forename: N J
authors.initials: NJ
authors.lastname: Anthony
authors.forename: M W
authors.initials: MW
authors.lastname: Conner
authors.forename: S J
authors.initials: SJ
authors.lastname: deSolms
authors.forename: T M
authors.initials: TM
authors.lastname: Williams
authors.forename: S L
authors.initials: SL
authors.lastname: Graham
authors.forename: G D
authors.initials: GD
authors.lastname: Hartman
authors.forename: A
authors.initials: A
authors.lastname: Oliff
mesh_terms: D019883:Alkyl and Aryl Transferases; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D014166:Transferases / Q000037:antagonists & inhibitors*; D018631:ras Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006160:Guanosine Triphosphate; D014166:Transferases; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D018631:ras Proteins