Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 84, Issue -, Pages 77-89Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.06.062
Keywords
Phosphonocarboxylates; Bisphosphonates; Geranylgeranylation; RGGT; GGPPS
Categories
Funding
- Ministry of Science and Higher Education in Poland [N N204 519839, IP2010 003070]
- Alliance for Better Bone Health
- graduate school, National Doctoral Programme in Informational and Structural Biology (ISB)
- Academy of Finland [252381]
- Sigrid Juselius Foundation
- Cancer Society of Finland
- Marie-Curie Reintegration Grant
- Versus Arthritis [17285] Funding Source: researchfish
- Academy of Finland (AKA) [252381, 252381] Funding Source: Academy of Finland (AKA)
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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. (c) 2014 Elsevier Masson SAS. All rights reserved.
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