title: Farnesyltransferase inhibitors. Preclinical development.
abstract: The Ras proteins are low molecular weight GTP binding proteins that function in the regulation of the transduction of growth proliferative signals from the membrane to the nucleus. Oncogenically mutated ras genes are found in approximately 25% of all human cancers. Localization of the Ras oncoproteins to the inner surface of the plasma membrane is essential for their biological activity. This observation suggested that the enzyme that mediates the membrane localization, farnesyl-protein transferase (FPTase), would be a target for the development of novel anticancer agents. We have developed potent, cell-active inhibitors of FPTase that exhibit antiproliferative activity in cell culture and block the morphologic alterations associated with Ras-induced transformation of mammalian cells in monolayer cultures. In vivo, these compounds block the growth of ras-transformed fibroblasts in a nude mouse xenograft model and block the growth and, in some cases, cause regression of mammary and salivary tumors in several strains of ras transgenic mice in the absence of any detectable side effects. The results of our preclinical studies and those of others suggest that FTIs may have utility against a variety of human cancers, a hypothesis that is currently being tested in the clinic.
authors.affiliation: Department of Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. nancy_kohl@merck.com
authors.forename: N E
authors.initials: NE
authors.lastname: Kohl
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D006801:Humans
chemical_list: D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase