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.
authors.affiliation: Musculoskeletal Programme, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB252ZD, UK.
authors.forename: Fraser P
authors.initials: FP
authors.lastname: Coxon
authors.affiliation: Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Joachimiak
authors.affiliation: Turku Centre for Biotechnology, Åbo Akademi University, Tykistökatu 6B, 20520 Turku, Finland.
authors.forename: Arafath Kaja
authors.initials: AK
authors.lastname: Najumudeen
authors.affiliation: Musculoskeletal Programme, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB252ZD, UK.
authors.forename: George
authors.initials: G
authors.lastname: Breen
authors.affiliation: Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Gmach
authors.affiliation: Turku Centre for Biotechnology, Åbo Akademi University, Tykistökatu 6B, 20520 Turku, Finland.
authors.forename: Christina
authors.initials: C
authors.lastname: Oetken-Lindholm
authors.affiliation: Musculoskeletal Programme, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB252ZD, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Way
authors.affiliation: University of Oxford, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, The Botnar Research Center, UK.
authors.forename: James E
authors.initials: JE
authors.lastname: Dunford
authors.affiliation: Turku Centre for Biotechnology, Åbo Akademi University, Tykistökatu 6B, 20520 Turku, Finland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Abankwa
authors.affiliation: Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland. Electronic address: katarzyna.blazewska@p.lodz.pl.
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Błażewska
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002417:Cattle; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D063065:Organophosphonates; D019883:Alkyl and Aryl Transferases; C075607:Rab geranylgeranyltransferase
keywords: Bisphosphonates; GGPPS; Geranylgeranylation; Phosphonocarboxylates; RGGT