title: Design and in vivo analysis of potent non-thiol inhibitors of farnesyl protein transferase.
abstract: Inhibitors of farnesyl protein transferase (FPTase) based upon a pseudotripeptide template are described that comprise an imidazole group substituted with a hydrophobic substituent. (1, 5)-Disubstitution of the imidazole group is shown to be the optimal array that leads to potent and selective inhibitors of FPTase. A variety of aryl and isoprenyl substituents are shown to afford effective inhibitors, and the mechanism by which these compounds inhibit FPTase has been investigated. The biochemical behavior of these compounds suggests that they bind to FPTase at the site usually occupied by the protein substrate. In experiments in cell culture, the methyl ester prodrugs of these inhibitors are cell permeant and potently inhibit the posttranslational modification of H-Ras protein. Additionally, these molecules revert the phenotype of ras transformed cells as evidenced by their ability to slow the growth of ras transformed cell lines in soft agar. One of the inhibitors, as its methyl prodrug, was evaluated in two in vivo models of tumor growth. The compound selectively inhibited the growth of tumors derived from H-ras transformed cells, in nude mice, and caused the regression of preexisting tumors in an H-ras transgenic animal model.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Anthony
authors.forename: R P
authors.initials: RP
authors.lastname: Gomez
authors.forename: M D
authors.initials: MD
authors.lastname: Schaber
authors.forename: S D
authors.initials: SD
authors.lastname: Mosser
authors.forename: K A
authors.initials: KA
authors.lastname: Hamilton
authors.forename: T J
authors.initials: TJ
authors.lastname: O'Neil
authors.forename: K S
authors.initials: KS
authors.lastname: Koblan
authors.forename: S L
authors.initials: SL
authors.lastname: Graham
authors.forename: G D
authors.initials: GD
authors.lastname: Hartman
authors.forename: D
authors.initials: D
authors.lastname: Shah
authors.forename: E
authors.initials: E
authors.lastname: Rands
authors.forename: N E
authors.initials: NE
authors.lastname: Kohl
authors.forename: J B
authors.initials: JB
authors.lastname: Gibbs
authors.forename: A I
authors.initials: AI
authors.lastname: Oliff
mesh_terms: D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002461:Cell Line, Transformed; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011355:Prodrugs; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D016283:Proto-Oncogene Proteins p21(ras)