Inhibition of farnesyltransferase with A-176120, a novel and potent farnesyl pyrophosphate analogue

Farnesylation of Ras is required for its transforming activity in human can cer and the reaction is catalysed by the enzyme farnesyltransferase. Recent ly, we discovered a novel chemical series of potent farnesyl pyrophosphate (FPP) analogues which selectively inhibited farnesyltransferase. Our most p otent compound to date in this series, A-176120, selectively inhibited farn esyltransferase activity (IC50 1.2+/-0.3 nM) over the closely related enzym es geranylgeranyltransferase I (GGTaseI) (IC50 423+/-1.8 nM), geranylgerany ltransferase II (GGTaseII) (IC50 3000 nM) and squalene synthase (SSase) (IC 50 > 10 000 nM). A-176120 inhibited ras processing in II-las-transformed NI H3T3 cells and HCT116 K-ras-mutated cells (ED50 1.6 and 0.5 mu M, respectiv ely). The anti angiogenic potential of A-176120 was demonstrated by a decre ase in Ras processing, cell proliferation and capillary structure formation of human umbilical vein endothelial cells (HUVEC), and a decrease in the s ecretion of vascular endothelial growth factor (VEGF) from HCT116 cells. In vivo, A-176120 reduced H-ras NIH3T3 tumour growth and extended the lifespa n of nude mice inoculated with H- or K-ras-transformed NIH3T3 cells. A-1761 20 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 reser ved.