title: A highly potent and selective farnesyltransferase inhibitor ABT-100 in preclinical studies.
abstract: Ras mutation has been detected in approximately 20-30% of all human carcinomas, primarily in pancreatic, colorectal, lung and bladder carcinomas. The indirect inhibition of Ras activity by inhibiting farnesyltransferase (FTase) function is one therapeutic intervention to control tumor growth. Here we report the preclinical anti-tumor activity of our most advanced FTase inhibitor (FTI), ABT-100, and a direct comparison with the current clinical candidates. ABT-100 is a highly selective, potent and orally bioavailable FTI. It broadly inhibits the growth of solid tumors in preclinical animal models. Thus, ABT-100 is an attractive candidate for further clinical evaluation. In addition, our results provide plausible insights to explain the impressive potency and selectivity of ABT-100. Finally, we have demonstrated that ABT-100 significantly suppresses the expression of vascular endothelial growth factor (VEGF) mRNA and secretion of VEGF protein, as well as inhibiting angiogenesis in the animal model.
authors.affiliation: Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
authors.forename: Wen-Zhen
authors.initials: WZ
authors.lastname: Gu
authors.forename: Ingrid
authors.initials: I
authors.lastname: Joseph
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Wang
authors.forename: David
authors.initials: D
authors.lastname: Frost
authors.forename: Gerard M
authors.initials: GM
authors.lastname: Sullivan
authors.forename: Le
authors.initials: L
authors.lastname: Wang
authors.forename: Nan-Horng
authors.initials: NH
authors.lastname: Lin
authors.forename: Jerry
authors.initials: J
authors.lastname: Cohen
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Stoll
authors.forename: Clarissa G
authors.initials: CG
authors.lastname: Jakob
authors.forename: Steven W
authors.initials: SW
authors.lastname: Muchmore
authors.forename: John E
authors.initials: JE
authors.lastname: Harlan
authors.forename: Tom
authors.initials: T
authors.lastname: Holzman
authors.forename: Karl A
authors.initials: KA
authors.lastname: Walten
authors.forename: Uri S
authors.initials: US
authors.lastname: Ladror
authors.forename: Mark G
authors.initials: MG
authors.lastname: Anderson
authors.forename: Paul
authors.initials: P
authors.lastname: Kroeger
authors.forename: Luis E
authors.initials: LE
authors.lastname: Rodriguez
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Jarvis
authors.forename: Debra
authors.initials: D
authors.lastname: Ferguson
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.forename: Shichung
authors.initials: S
authors.lastname: Ng
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016510:Corneal Neovascularization / Q000188:drug therapy; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000037:antagonists & inhibitors*
chemical_list: C503142:ABT-100; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D051231:Farnesyltranstransferase; D018631:ras Proteins