In vitro studies in a myelogenous leukemia cell line suggest an organized binding of geranylgeranyl diphosphate synthase inhibitors

Biochem Pharmacol. 2015 Jul 15;96(2):83-92. doi: 10.1016/j.bcp.2015.04.009. Epub 2015 May 4.


A small set of isoprenoid bisphosphonates ethers has been tested in the K562 chronic myelogenous leukemia cell line to determine their impact on isoprenoid biosynthesis. Five of these compounds inhibit geranylgeranyl diphosphate synthase (GGDPS) with IC50 values below 1 μM in enzyme assays, but in cells their apparent activity is more varied. In particular, the isomeric C-geranyl-O-prenyl and C-prenyl-O-geranyl bisphosphonates are quite different in their activity with the former consistently demonstrating greater impairment of geranylgeranylation in cells but the latter showing greater impact in the enzyme assays with GGDPS. Together, these findings suggest an organized binding of these inhibitors in the two hydrophobic channels of the geranylgeranyl diphosphate synthase enzyme.

Keywords: Bisphosphonate; Chronic myelogenous leukemia (CML); Geranylgeranyl diphosphate synthase; Isoprenoid; Protein isoprenylation; Statin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Diphosphonates / chemistry
  • Diphosphonates / pharmacology*
  • Ethers / chemistry
  • Ethers / pharmacology*
  • Farnesyltranstransferase / antagonists & inhibitors*
  • Humans
  • K562 Cells
  • Polyisoprenyl Phosphates / metabolism
  • Protein Binding
  • Protein Prenylation
  • Structure-Activity Relationship
  • Terpenes / chemistry
  • Terpenes / pharmacology*
  • rab GTP-Binding Proteins / metabolism
  • rap1 GTP-Binding Proteins / metabolism
  • ras Proteins / metabolism


  • Diphosphonates
  • Ethers
  • Polyisoprenyl Phosphates
  • Rab6 protein
  • Terpenes
  • Farnesyltranstransferase
  • rab GTP-Binding Proteins
  • rap1 GTP-Binding Proteins
  • ras Proteins
  • geranylgeranyl pyrophosphate