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

doi:10.1016/j.ejmech.2014.06.062

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

Medical Sciences

Research output: Contribution to journal › Article › peer-review

24 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 language	English
Pages (from-to)	77-89
Number of pages	13
Journal	European Journal of Medicinal Chemistry
Volume	84
Early online date	28 Jun 2014
DOIs	https://doi.org/10.1016/j.ejmech.2014.06.062
Publication status	Published - 12 Sept 2014

Bibliographical note

Copyright © 2014 Elsevier Masson SAS. All rights reserved.

KMB is grateful for financial support provided by Ministry of Science and Higher Education in Poland (N N204 519839 and IP2010 003070). FPC is grateful for financial support from the Alliance for Better Bone Health. AKN is grateful for support by the graduate school, National Doctoral Programme in Informational and Structural Biology (ISB). This work was supported by the Academy of Finland (252381) fellowship grant, the Sigrid Juselius Foundation, the Cancer Society of Finland and the Marie-Curie Reintegration Grant to DA.

The authors thank Prof. Tadeusz Gajda and Prof. Charles E. McKenna for helpful discussions, Ms. Marzena Kujawa for technical assistance, Jonna Alanko for cloning of the Rab21-NANOPS.

Keywords

phosphonocarboxylates
bisphosphonates
geranylgeranylation
RGGT
GGPPS

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejmech.2014.06.062

Cite this

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title = "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.",

keywords = "phosphonocarboxylates, bisphosphonates, geranylgeranylation, RGGT, GGPPS",

author = "Fraser Coxon and Lukasz Joachimiak and Najumudeen, {Arafath Kaja} and George Breen and Joanna Gmach and Christina Oetken-Lindholm and Rebecca Way and Dunford, {James E} and Daniel Abankwa and B{\l}a{\.z}ewska, {Katarzyna M}",

note = "Copyright {\textcopyright} 2014 Elsevier Masson SAS. All rights reserved. KMB is grateful for financial support provided by Ministry of Science and Higher Education in Poland (N N204 519839 and IP2010 003070). FPC is grateful for financial support from the Alliance for Better Bone Health. AKN is grateful for support by the graduate school, National Doctoral Programme in Informational and Structural Biology (ISB). This work was supported by the Academy of Finland (252381) fellowship grant, the Sigrid Juselius Foundation, the Cancer Society of Finland and the Marie-Curie Reintegration Grant to DA. The authors thank Prof. Tadeusz Gajda and Prof. Charles E. McKenna for helpful discussions, Ms. Marzena Kujawa for technical assistance, Jonna Alanko for cloning of the Rab21-NANOPS.",

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doi = "10.1016/j.ejmech.2014.06.062",

language = "English",

volume = "84",

pages = "77--89",

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T1 - Synthesis and characterization of novel phosphonocarboxylate inhibitors of RGGT

AU - Coxon, Fraser

AU - Joachimiak, Lukasz

AU - Najumudeen, Arafath Kaja

AU - Breen, George

AU - Gmach, Joanna

AU - Oetken-Lindholm, Christina

AU - Way, Rebecca

AU - Dunford, James E

AU - Abankwa, Daniel

AU - Błażewska, Katarzyna M

N1 - Copyright © 2014 Elsevier Masson SAS. All rights reserved. KMB is grateful for financial support provided by Ministry of Science and Higher Education in Poland (N N204 519839 and IP2010 003070). FPC is grateful for financial support from the Alliance for Better Bone Health. AKN is grateful for support by the graduate school, National Doctoral Programme in Informational and Structural Biology (ISB). This work was supported by the Academy of Finland (252381) fellowship grant, the Sigrid Juselius Foundation, the Cancer Society of Finland and the Marie-Curie Reintegration Grant to DA. The authors thank Prof. Tadeusz Gajda and Prof. Charles E. McKenna for helpful discussions, Ms. Marzena Kujawa for technical assistance, Jonna Alanko for cloning of the Rab21-NANOPS.

PY - 2014/9/12

Y1 - 2014/9/12

N2 - 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.

AB - 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.

KW - phosphonocarboxylates

KW - bisphosphonates

KW - geranylgeranylation

KW - RGGT

KW - GGPPS

U2 - 10.1016/j.ejmech.2014.06.062

DO - 10.1016/j.ejmech.2014.06.062

M3 - Article

C2 - 25016230

SN - 0223-5234

VL - 84

SP - 77

EP - 89

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

Synthesis and characterization of novel phosphonocarboxylate inhibitors of RGGT

Abstract

Bibliographical note

Keywords

UN SDGs

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