title: Antitumor activity of ER-51785, a new peptidomimetic inhibitor of farnesyl transferase: synergistic effect in combination with paclitaxel.
abstract: Inhibitors of ras farnesylation have been extensively studied in the preclinical stage, and some of them are being developed in the clinic. Herein, we describe the antitumor activity of a new farnesyl transferase inhibitor, ER-51785. In vitro, ER-51785 selectively inhibited farnesyl transferase activity (IC50 = 77 nM) compared with geranylgeranyl transferase I activity (IC50 = 4200 nM). In cells, ER-51785 inhibited posttranslational processing of H-ras with IC50 = 28 nM, but not that of rap 1A at concentrations up to 50 microM. This compound also strongly inhibited colony formation of H-ras-transformed NIH 3T3 fibroblasts and EJ-1 bladder carcinoma cells. In vivo, ER-51785 showed potent tumor regression activity against EJ-1 xenografts but only modest activity against MIA PaCa-2 xenografts. Treatment of ER-51785 in combination with paclitaxel exhibited synergistic effects against colony formation and tumor growth of MIA PaCa-2 cells. The results presented herein support the idea that farnesyl transferase inhibitors alone and in combination with other chemotherapeutic agents have the potential to be developed as therapies for tumors expressing H-ras or K-ras oncogenes.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan. k2-nakamura@hhc.eisai.co.jp
authors.forename: K
authors.initials: K
authors.lastname: Nakamura
authors.forename: A
authors.initials: A
authors.lastname: Yamaguchi
authors.forename: M
authors.initials: M
authors.lastname: Namiki
authors.forename: H
authors.initials: H
authors.lastname: Ishihara
authors.forename: T
authors.initials: T
authors.lastname: Nagasu
authors.forename: J J
authors.initials: JJ
authors.lastname: Kowalczyk
authors.forename: A M
authors.initials: AM
authors.lastname: Garcia
authors.forename: M D
authors.initials: MD
authors.lastname: Lewis
authors.forename: K
authors.initials: K
authors.lastname: Yoshimatsu
mesh_terms: D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051231:Farnesyltranstransferase; D011905:Genes, ras / Q000187:drug effects; D006801:Humans; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C465021:ER 51785; D004791:Enzyme Inhibitors; D008715:Methionine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D017239:Paclitaxel