Synthesis and characterization of novel phosphonocarboxylate inhibitors of RGGT

Eur J Med Chem. 2014 Sep 12;84:77-89. doi: 10.1016/j.ejmech.2014.06.062. Epub 2014 Jun 28.

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.

Keywords: Bisphosphonates; GGPPS; Geranylgeranylation; Phosphonocarboxylates; RGGT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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