Inhibition of Farnesyltransferase with A-176120, A Novel and Potent Farnesyl Pyrophosphate Analogue
European journal of cancer(2000)
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 (IC50 1.2+/-0.3 nM) over the closely related enzymes geranylgeranyltransferase I (GGTaseI) (IC50 423+/-1.8 nM), geranylgeranyltransferase II (GGTaseII) (IC50 3000 nM) and squalene synthase (SSase) (IC50 > 10 000 nM). A-176120 inhibited ras processing in II-las-transformed NIH3T3 cells and HCT116 K-ras-mutated cells (ED50 1.6 and 0.5 mu M, 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. (C) 2000 Elsevier Science Ltd. All rights reserved.
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Key words
farnesyltransferase,farnesyl pyrophosphate analogue,angiogenesis,Ras processing,vascular endothelial growth factor,squalene synthase,cyclophosphamide,human tumour xenograft
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