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 journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)77-89
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume84
Early online date28 Jun 2014
DOIs
Publication statusPublished - 12 Sep 2014

Fingerprint

Diphosphonates
Skin Neoplasms
Enzymes
Ovarian Neoplasms
Skin
Breast Neoplasms
Derivatives
Pharmaceutical Preparations
Rab geranylgeranyltransferase
diphosphoric acid
prenyl

Keywords

  • phosphonocarboxylates
  • bisphosphonates
  • geranylgeranylation
  • RGGT
  • GGPPS

Cite this

Coxon, F., Joachimiak, L., Najumudeen, A. K., Breen, G., Gmach, J., Oetken-Lindholm, C., ... Błażewska, K. M. (2014). Synthesis and characterization of novel phosphonocarboxylate inhibitors of RGGT. European Journal of Medicinal Chemistry, 84, 77-89. https://doi.org/10.1016/j.ejmech.2014.06.062

Synthesis and characterization of novel phosphonocarboxylate inhibitors of RGGT. / Coxon, Fraser; Joachimiak, Lukasz; Najumudeen, Arafath Kaja; Breen, George; Gmach, Joanna; Oetken-Lindholm, Christina; Way, Rebecca; Dunford, James E; Abankwa, Daniel; Błażewska, Katarzyna M.

In: European Journal of Medicinal Chemistry, Vol. 84, 12.09.2014, p. 77-89.

Research output: Contribution to journalArticle

Coxon, F, Joachimiak, L, Najumudeen, AK, Breen, G, Gmach, J, Oetken-Lindholm, C, Way, R, Dunford, JE, Abankwa, D & Błażewska, KM 2014, 'Synthesis and characterization of novel phosphonocarboxylate inhibitors of RGGT', European Journal of Medicinal Chemistry, vol. 84, pp. 77-89. https://doi.org/10.1016/j.ejmech.2014.06.062
Coxon, Fraser ; Joachimiak, Lukasz ; Najumudeen, Arafath Kaja ; Breen, George ; Gmach, Joanna ; Oetken-Lindholm, Christina ; Way, Rebecca ; Dunford, James E ; Abankwa, Daniel ; Błażewska, Katarzyna M. / Synthesis and characterization of novel phosphonocarboxylate inhibitors of RGGT. In: European Journal of Medicinal Chemistry. 2014 ; Vol. 84. pp. 77-89.
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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.",
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AU - Joachimiak, Lukasz

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AU - Gmach, Joanna

AU - Oetken-Lindholm, Christina

AU - Way, Rebecca

AU - Dunford, James E

AU - Abankwa, Daniel

AU - Błażewska, Katarzyna M

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