Potent Triazole Bisphosphonate Inhibitor of Geranylgeranyl Diphosphate Synthase

Wills, Veronica S.; Allen, Cheryl; Holstein, Sarah A.; Wiemer, David F.

doi:10.1021/acsmedchemlett.5b00334

Cited by 43 publications

(67 citation statements)

References 17 publications

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“…Cell culture studies were performed to determine the relative potencies of the HG and HN isomers in disrupting geranylgeranylation. We previously demonstrated that inhibition of Rab geranylgeranylation results in accumulation of intracellular monoclonal protein levels in myeloma cells and that changes in this protein level can be used as a surrogate marker for disruption of geranylgeranylation (Holstein and Hohl, 2011;Wills et al, 2015). An ELISA analysis of lambda light chain levels after treatment with either HG or HN in MM cells and MM.1S (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

“…2). Because the original mixture is a 3:1 ratio in favor of the less potent isomer (3:1 HG:HN) (Wills et al, 2015), these results suggested that the two isomers might interact with each other. Therefore, studies were performed in which cells were incubated with varying combinations of HN and HG.…”

Section: Inhibition Of Geranylgeranyl Diphosphate Synthasementioning

confidence: 94%

“…[ 14 C]-IPP was purchased from American Radiolabeled Chemicals (St. Louis, MO). The pure homogeranyl and homoneryl triazole bisphosphonates (7 and 8) and the 3:1 (HG:HN) mixture (6) were prepared as previously reported (Wills et al, 2015;Matthiesen et al, 2016). Stock solutions (50 mM) of the triazole bisphosphonate sodium salts were prepared in sterile water and stored at 220°C.…”

Section: Methodsmentioning

confidence: 99%

“…Recombinant GGDPS was obtained from MyBioSource (San Diego, CA). Enzyme assays were performed as previously described (Wills et al, 2015). Compounds were tested in duplicate and three independent experiments were performed.…”

Section: Methodsmentioning

confidence: 99%

“…Subsequently a preparation of a homogeranyl/homoneryl triazole bisphosphonate mixture ( Fig. 1) was identified as the most potent inhibitor of GGDPS described to date with an IC 50 of 45 nM (Wills et al, 2015). Given the relative activities of the geranyl/neryl isomers, one might predict that the homoneryl isomer would be significantly more potent than the homogeranyl isomer, and efforts have therefore been focused on the preparation of the pure isomers (Matthiesen et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

et al. 2017

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The isoprenoid donor for protein geranylgeranylation reactions, geranylgeranyl diphosphate (GGDP), is the product of the enzyme GGDP synthase (GGDPS) that condenses farnesyl diphosphate (FDP) and isopentenyl pyrophosphate. GGDPS inhibition is of interest from a therapeutic perspective for multiple myeloma because we have shown that targeting Rab GTPase geranylgeranylation impairs monoclonal protein trafficking, leading to endoplasmic reticulum stress and apoptosis. We reported a series of triazole bisphosphonate GGDPS inhibitors, of which the most potent was a 3:1 mixture of homogeranyl (HG) and homoneryl (HN) isomers. Here we determined the activity of the individual olefin isomers. Enzymatic and cellular assays revealed that although HN is approximately threefold more potent than HG, HN is not more potent than the original mixture. Studies in which cells were treated with varying concentrations of each isomer alone and in different combinations revealed that the two isomers potentiate the induced-inhibition of protein geranylgeranylation when used in a 3:1 HG:HN combination. A synergistic interaction was observed between the two isomers in the GGDPS enzyme assay. These results suggested that the two isomers bind simultaneously to the enzyme but within different domains. Computational modeling studies revealed that HN is preferred at the FDP site, that HG is preferred at the GGDP site, and that both isomers may bind to the enzyme simultaneously. These studies are the first to report a set of olefin isomers that synergistically inhibit GGDPS, thus establishing a new paradigm for the future development of GGDPS inhibitors.

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Section: Resultsmentioning

confidence: 99%

Section: Inhibition Of Geranylgeranyl Diphosphate Synthasementioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

et al. 2017

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Diketopyrrolopyrrole Bis‐Phosphonate Conjugate: A New Fluorescent Probe for In Vitro Bone Imaging

Chiminazzo

Borsato

Favero³

et al. 2019

Chemistry A European J

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The synthesis of a conjugate molecule between an unusual red‐fluorescent diketopyrrolopyrrole (DPP) unit and a bis‐phosphonate (BP) precursor by a click‐chemistry strategy to target bone tissue and monitor the interaction is reported. After thorough investigation, conjugation through a triazole unit between a γ‐azido rather than a β‐azido BP and an alkyne‐functionalized DPP fluorophore group turned out to be the winning strategy. Visualization of the DPP‐BP conjugate on osteoclasts and specific antiresorption activity were successfully demonstrated.

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Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target

Muehlebach

Holstein

2023

Clinical & Translational Med

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Geranylgeranyl diphosphate synthase (GGDPS), an enzyme in the isoprenoid biosynthesis pathway, is responsible for the production of geranylgeranyl pyrophosphate (GGPP). GGPP serves as a substrate for the post‐translational modification (geranylgeranylation) of proteins, including those belonging to the Ras superfamily of small GTPases. These proteins play key roles in signalling pathways, cytoskeletal regulation and intracellular transport, and in the absence of the prenylation modification, cannot properly localise and function. Aberrant expression of GGDPS has been implicated in various human pathologies, including liver disease, type 2 diabetes, pulmonary disease and malignancy. Thus, this enzyme is of particular interest from a therapeutic perspective. Here, we review the physiological function of GGDPS as well as its role in pathophysiological processes. We discuss the current GGDPS inhibitors under development and the therapeutic implications of targeting this enzyme.

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Potent Triazole Bisphosphonate Inhibitor of Geranylgeranyl Diphosphate Synthase

Cited by 43 publications

References 17 publications

Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

Diketopyrrolopyrrole Bis‐Phosphonate Conjugate: A New Fluorescent Probe for In Vitro Bone Imaging

Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target

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