Synthesis and characterization of novel phosphonocarboxylate inhibitors of RGGT.

Abstract

Phosphonocarboxylate (PC) analogs of the anti-osteoporotic drugs, bisphosphonates, represent the first class of selective inhibitors of Rab geranylgeranyl transferase (RabGGTase, RGGT), an enzyme implicated in several diseases including ovarian, breast and skin cancer. Here we present the synthesis and biological characterization of an extended set of this class of compounds, including lipophilic derivatives of the known RGGT inhibitors. From this new panel of PCs, we have identified an inhibitor of RGGT that is of similar potency as the most active published phosphonocarboxylate, but of higher selectivity towards this enzyme compared to prenyl pyrophosphate synthases. New insights into structural requirements are also presented, showing that only PC analogs of the most potent 3rd generation bisphosphonates inhibit RGGT. In addition, the first phosphonocarboxylate-derived GGPPS inhibitor is reported.

• Authors: Fraser P Coxon, Lukasz Joachimiak, Arafath Kaja Najumudeen, George Breen, Joanna Gmach, Christina Oetken-Lindholm, Rebecca Way, James E Dunford, Daniel Abankwa, Katarzyna M Błażewska
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 84 Pg. 77-89 (Sep 12 2014) ISSN: 1768-3254 [Electronic] France
• PMID: 25016230 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Organophosphonates
• Alkyl and Aryl Transferases
• Rab geranylgeranyltransferase

Topics

• Alkyl and Aryl Transferases (antagonists & inhibitors, metabolism)
• Animals
• Cattle
• Cell Line
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• HeLa Cells
• Humans
• Molecular Structure
• Organophosphonates (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship