Lipophilic Bisphosphonates as Dual Farnesyl/Geranylgeranyl Diphosphate Synthase Inhibitors: An X-ray and NMR Investigation
- 23 March 2009
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 131 (14), 5153-5162
- https://doi.org/10.1021/ja808285e
Abstract
Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS.This publication has 37 references indexed in Scilit:
- Endocrine Therapy plus Zoledronic Acid in Premenopausal Breast CancerThe New England Journal of Medicine, 2009
- Bisphosphonate Inhibition of a Plasmodium Farnesyl Diphosphate Synthase and a General Method for Predicting Cell-Based Activity from Enzyme DataJournal of Medicinal Chemistry, 2008
- Zoledronic acid-induced IPP/ApppI production in vivoLife Sciences, 2007
- Bisphosphonates target multiple sites in both cis - and trans -prenyltransferasesProceedings of the National Academy of Sciences of the United States of America, 2007
- Digeranyl bisphosphonate inhibits geranylgeranyl pyrophosphate synthaseBiochemical and Biophysical Research Communications, 2007
- The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugsProceedings of the National Academy of Sciences of the United States of America, 2006
- Inhibitory effects of a new bisphosphonate, minodronate, on proliferation and invasion of a variety of malignant bone tumor cellsJournal of Orthopaedic Research, 2006
- Coot: model-building tools for molecular graphicsActa crystallographica. Section D, Structural biology, 2004
- Nitrogen-Containing Bisphosphonates as Carbocation Transition State Analogs for Isoprenoid BiosynthesisBiochemical and Biophysical Research Communications, 1999
- XtalView/Xfit—A Versatile Program for Manipulating Atomic Coordinates and Electron DensityJournal of Structural Biology, 1999