title: Inhibition of human tumor cell growth in vitro and in vivo by a specific inhibitor of human farnesyltransferase: BIM-46068.
abstract: Oncogenic mutations of the ras gene leading to constitutive activation of downstream effectors have been detected in a large spectrum of human cancers (pancreas, thyroid, colon and NSCLC). Membrane anchorage of Ras required for functional activity in signal transduction is facilitated by post-translational modifications resulting in covalent attachment of a farnesyl group to the cysteine in the C-terminal CAAX motif. This attachment is mediated by farnesyltransferase (FTase). Here, we report a novel series of potent FTase inhibitors, where the tetrapeptide CAAX motif has been modified by incorporation of a thiazolidine carboxylic acid moiety followed by reduction of the 1st and 2nd peptide bonds to a secondary and tertiary amine, respectively. The C-terminal carboxylate was converted to esters for improved cellular penetration. These compounds showed specific inhibition of purified human FTase enzyme, inhibition of proliferation in vitro in a large spectrum of human tumor cell lines and inhibition of growth of human tumor xenografts in athymic nude mice. In addition, in regard to a panel of cell lines, using the Compare analysis to determine the Pearson coefficient correlation, the anti-proliferative spectrum of BIM-46068 has been shown to be distinct from the profile of typical chemotherapeutic agents.
authors.affiliation: Institut Henri Beaufour, Les Ulis, France. gregoire.prevost@beaufour-ipsen.com
authors.forename: G P
authors.initials: GP
authors.lastname: Prevost
authors.forename: A
authors.initials: A
authors.lastname: Pradines
authors.forename: I
authors.initials: I
authors.lastname: Viossat
authors.forename: M C
authors.initials: MC
authors.lastname: Brezak
authors.forename: K
authors.initials: K
authors.lastname: Miquel
authors.forename: M O
authors.initials: MO
authors.lastname: Lonchampt
authors.forename: P
authors.initials: P
authors.lastname: Kasprzyk
authors.forename: G
authors.initials: G
authors.lastname: Favre
authors.forename: B
authors.initials: B
authors.lastname: Pignol
authors.forename: C
authors.initials: C
authors.lastname: Le Breton
authors.forename: J
authors.initials: J
authors.lastname: Dong
authors.forename: B
authors.initials: B
authors.lastname: Morgan
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000598:Amino Acids, Cyclic / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D005260:Female; D011905:Genes, ras; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000598:Amino Acids, Cyclic; D000970:Antineoplastic Agents; C121833:BIM 46050; C121832:BIM 46068; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D018631:ras Proteins