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

Eur J Cancer. 2000 Jun;36(9):1161-70. doi: 10.1016/s0959-8049(00)00067-8.

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.

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Animals
  • Cell Division
  • Endothelial Growth Factors / metabolism
  • Endothelium, Vascular / cytology
  • Enzyme Inhibitors / pharmacology*
  • Farnesyl-Diphosphate Farnesyltransferase / antagonists & inhibitors
  • Farnesyltranstransferase
  • Genes, ras / genetics
  • Humans
  • Lymphokines / metabolism
  • Male
  • Mice
  • Mice, Nude
  • Mutation / genetics
  • Neoplasm Transplantation
  • Neovascularization, Pathologic
  • Polyisoprenyl Phosphates / pharmacology*
  • Sesquiterpenes
  • Transplantation, Heterologous
  • Tumor Cells, Cultured
  • Umbilical Veins / cytology
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Endothelial Growth Factors
  • Enzyme Inhibitors
  • Lymphokines
  • Polyisoprenyl Phosphates
  • Sesquiterpenes
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • farnesyl pyrophosphate
  • Alkyl and Aryl Transferases
  • Farnesyl-Diphosphate Farnesyltransferase
  • Farnesyltranstransferase