Synthesis and characterization of novel phosphonocarboxylate inhibitors of RGGT

Fraser Coxon, Lukasz Joachimiak, Arafath Kaja Najumudeen, George Breen, Joanna Gmach, Christina Oetken-Lindholm, Rebecca Way, James E Dunford, Daniel Abankwa, Katarzyna M Błażewska

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)77-89
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Early online date28 Jun 2014
Publication statusPublished - 12 Sep 2014


  • phosphonocarboxylates
  • bisphosphonates
  • geranylgeranylation
  • RGGT


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