Inhibition of farnesyltransferase with A-176120, a novel and potent farnesyl pyrophosphate analogue.
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.
Tahir
S K
SK
Cancer Research, Pharmaceutical Product Research Division, Abbott Laboratories, 100 Abbott Park Road, IL 60064, Abbott Park, USA.
Gu
W Z
WZ
Zhang
H C
HC
Leal
J
J
Lee
J Y
JY
Kovar
P
P
Saeed
B
B
Cherian
S P
SP
Devine
E
E
Cohen
J
J
Warner
R
R
Wang
Y C
YC
Stout
D
D
Arendsen
D L
DL
Rosenberg
S
S
Ng
S C
SC
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
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