title: Antitumor efficacy of a novel class of non-thiol-containing peptidomimetic inhibitors of farnesyltransferase and geranylgeranyltransferase I: combination therapy with the cytotoxic agents cisplatin, Taxol, and gemcitabine.
abstract: Ras malignant transformation requires posttranslational modification by farnesyltransferase (FTase). Here we report on the design and antitumor activity, in monotherapy as well as in combination therapy with cytotoxic agents, of a novel class of non-thiol-containing peptidomimetic inhibitors of FTase and the closely related family member geranylgeranyltransferase I (GGTase I). The non-thiol-containing FTI-2148 is highly selective for FTase (IC50, 1.4 nM) over GGTase I (IC50, 1700 nM), whereas GGTI-2154 is highly selective for GGTase I (21 nM) over FTase (IC50, 5600 nM). In whole cells, the corresponding methylester prodrug FTI-2153 is >3000-fold more potent at inhibiting H-Ras (IC50, 10 nM) than Rap1A processing, whereas GGTI-2166 is over 100-fold more selective at inhibiting Rap1A (IC50, 300 nM) over H-Ras processing. Furthermore, FTI-2153 was highly effective at suppressing oncogenic H-Ras constitutive activation of mitogen-activated protein kinase and human tumor growth in soft agar. FTI-2148 suppressed the growth of the human lung adenocarcinoma A-549 cells in nude mice by 33, 67, and 91% in a dose-dependent manner. Combination therapy of FTI-2148 with either cisplatin, gemcitabine, or Taxol resulted in a greater antitumor efficacy than monotherapy. GGTI-2154 in similar antitumor efficacy experiments is less potent than FTI-2148 and inhibits tumor growth by 9, 27, and 46%. Combination therapy of GGTI-2154 with cisplatin, gemcitabine, or Taxol is also more effective. Finally, FTI-2148 and GGTI-2154 are 30- and 33-fold more selective and 30- and 16-fold more potent in whole cells than our previously reported thiol-containing FTI-276 and GGTI-297, respectively. Thus, our results demonstrate that this highly potent and selective novel class of non-thiol-containing peptidomimetics inhibits human tumor growth in whole animals and that combination therapy with cytotoxic agents is more beneficial than monotherapy.
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Department of Biochemistry and Molecular Biology, University of South Florida, Tampa 33612, USA.
authors.forename: J
authors.initials: J
authors.lastname: Sun
authors.forename: M A
authors.initials: MA
authors.lastname: Blaskovich
authors.forename: D
authors.initials: D
authors.lastname: Knowles
authors.forename: Y
authors.initials: Y
authors.lastname: Qian
authors.forename: J
authors.initials: J
authors.lastname: Ohkanda
authors.forename: R D
authors.initials: RD
authors.lastname: Bailey
authors.forename: A D
authors.initials: AD
authors.lastname: Hamilton
authors.forename: S M
authors.initials: SM
authors.lastname: Sebti
mesh_terms: D016475:3T3 Cells; D000230:Adenocarcinoma / Q000188:drug therapy*; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D001549:Benzamides / Q000737:chemistry* / Q000627:therapeutic use* / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D051231:Farnesyltranstransferase; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D020827:rap1 GTP-Binding Proteins / Q000037:antagonists & inhibitors; D018631:ras Proteins / Q000037:antagonists & inhibitors; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; C102520:GGTI 297; D009842:Oligopeptides; D003841:Deoxycytidine; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; D020928:Mitogen-Activated Protein Kinases; D020827:rap1 GTP-Binding Proteins; D018631:ras Proteins; D017239:Paclitaxel; D002945:Cisplatin; D000093542:Gemcitabine