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Inhibition of Farnesyltransferase with A-176120, A Novel and Potent Farnesyl Pyrophosphate Analogue

European journal of cancer(2000)

Cited 21|Views22
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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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