title: Inhibition of farnesyltransferase with A-176120, a novel and potent farnesyl pyrophosphate analogue.
abstract: Farnesylation of Ras is required for its transforming activity in human cancer and the reaction is catalysed by the enzyme farnesyltransferase. Recently, we discovered a novel chemical series of potent farnesyl pyrophosphate (FPP) analogues which selectively inhibited farnesyltransferase. Our most potent compound to date in this series, A-176120, selectively inhibited farnesyltransferase activity (IC(50) 1.2+/-0.3 nM) over the closely related enzymes geranylgeranyltransferase I (GGTaseI) (IC(50) 423+/-1.8 nM), geranylgeranyltransferase II (GGTaseII) (IC(50) 3000 nM) and squalene synthase (SSase) (IC(50)>10000 nM). A-176120 inhibited ras processing in H-ras-transformed NIH3T3 cells and HCT116 K-ras-mutated cells (ED(50) 1.6 and 0.5 microM, respectively). The anti-angiogenic potential of A-176120 was demonstrated by a decrease in Ras processing, cell proliferation and capillary structure formation of human umbilical vein endothelial cells (HUVEC), and a decrease in the secretion of vascular endothelial growth factor (VEGF) from HCT116 cells. In vivo, A-176120 reduced H-ras NIH3T3 tumour growth and extended the lifespan of nude mice inoculated with H- or K-ras-transformed NIH3T3 cells. A-176120 also had an additive effect in combination with cyclophosphamide in nude mice inoculated with K-ras NIH3T3 transformed cells. Overall, our results demonstrate that A-176120 is a potent FPP mimetic with both antitumour and anti-angiogenic properties.
authors.affiliation: Cancer Research, Pharmaceutical Product Research Division, Abbott Laboratories, 100 Abbott Park Road, IL 60064, Abbott Park, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Tahir
authors.forename: W Z
authors.initials: WZ
authors.lastname: Gu
authors.forename: H C
authors.initials: HC
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Leal
authors.forename: J Y
authors.initials: JY
authors.lastname: Lee
authors.forename: P
authors.initials: P
authors.lastname: Kovar
authors.forename: B
authors.initials: B
authors.lastname: Saeed
authors.forename: S P
authors.initials: SP
authors.lastname: Cherian
authors.forename: E
authors.initials: E
authors.lastname: Devine
authors.forename: J
authors.initials: J
authors.lastname: Cohen
authors.forename: R
authors.initials: R
authors.lastname: Warner
authors.forename: Y C
authors.initials: YC
authors.lastname: Wang
authors.forename: D
authors.initials: D
authors.lastname: Stout
authors.forename: D L
authors.initials: DL
authors.lastname: Arendsen
authors.forename: S
authors.initials: S
authors.lastname: Rosenberg
authors.forename: S C
authors.initials: SC
authors.lastname: Ng
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D002455:Cell Division; D016228:Endothelial Growth Factors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors; D051231:Farnesyltranstransferase; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology*; D012717:Sesquiterpenes; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D008222:Lymphokines; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C004808:farnesyl pyrophosphate; D019883:Alkyl and Aryl Transferases; D013186:Farnesyl-Diphosphate Farnesyltransferase; D051231:Farnesyltranstransferase