Synthesis and biological activity of isoprenoid bisphosphonates

Shull, Larry W.; Wiemer, Andrew J.; Hohl, Raymond J.; Wiemer, David F.

doi:10.1016/j.bmc.2006.02.010

Cited by 76 publications

(81 citation statements)

References 19 publications

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“…DNA Synthesis Assays. K562 cells were incubated in 96-well plates and treated with compounds as described previously (Shull et al, 2006). After 22 h, 20 l of [ 3 H]thymidine (0.1385 TBq/mmol; 3.75 Ci/mmol in media) was added to each well.…”

Section: Methodsmentioning

confidence: 99%

“…However, their cellular effects, including induction of apoptosis, may be largely a result of downstream GGPP depletion (Fisher et al, 1999;van Beek et al, 1999a). Based on this rationale, we developed a series of isoprenoid-containing bisphosphonates that specifically inhibit geranylgeranyl diphosphate synthase (GGDPS) (Shull et al, 2006;Maalouf et al, 2007;Wiemer et al, 2007). We have shown that several of these compounds, including digeranyl bisphosphonate (DGBP), can potently inhibit GGDPS in vitro .…”

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confidence: 99%

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Inhibition of Geranylgeranyl Diphosphate Synthase Induces Apoptosis through Multiple Mechanisms and Displays Synergy with Inhibition of Other Isoprenoid Biosynthetic Enzymes

Dudakovic

Wiemer

Lamb

et al. 2007

J Pharmacol Exp Ther

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Inhibitors of isoprenoid synthesis are widely used for treatment of human diseases, including hypercholesterolemia and osteoporosis, and they have the potential to be useful for treatment of cancer. Statin drugs inhibit the enzyme HMG-CoA reductase, whereas nitrogenous bisphosphonates have more recently been shown to inhibit farnesyl disphosphate synthase. In addition, our laboratory has recently developed several potent and specific bisphosphonate inhibitors of geranylgeranyl diphosphate synthase, including digeranyl bisphosphonate. Because all three enzymes fall in the same biosynthetic pathway and many of the biological effects are due to depletion of downstream products, we hypothesized that simultaneous inhibition of these enzymes would result in synergistic growth inhibition. In this study, we show that inhibition of geranylgeranyl diphosphate synthase induces apoptosis in K562 leukemia cells. This induction of apoptosis is in part dependent upon both geranylgeranyl diphosphate depletion and accumulation of farnesyl diphosphate. Combinations of either lovastatin or zoledronate with digeranyl bisphosphonate synergistically inhibited growth and induced apoptosis. These combinations also potently inhibited cellular geranylgeranylation. These results support the potential for combinations of multiple inhibitors of isoprene biosynthesis to inhibit cancer cell growth or metastasis at clinically achievable concentrations.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Inhibition of Geranylgeranyl Diphosphate Synthase Induces Apoptosis through Multiple Mechanisms and Displays Synergy with Inhibition of Other Isoprenoid Biosynthetic Enzymes

Dudakovic

Wiemer

Lamb

et al. 2007

J Pharmacol Exp Ther

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“…Our laboratories previously identifi ed geranyl bisphosphonate ( 33 ) as an inhibitor of GGDPS ( 34 ). With this in mind, we set out to determine whether the compounds active against SQS impaired protein farnesylation or geranylgeranylation, outputs that can identify inhibitors of FDPS, GGDPS, or prenyltransferases ( 35,36 ).…”

Section: Effects Of Compounds 1-5 On Protein Prenylation In Hepg2 Cellsmentioning

confidence: 99%

A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro

Wasko

Smits

Shull

et al. 2011

Journal of Lipid Research

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“…1), which was found to have an IC 50 of 260 nM against the enzyme (Shull et al, 2006;Wiemer et al, 2007). Crystallography studies revealed that the V-shaped compound occupied the FDP substrate binding site as well as the GGDP product site within the enzyme's active site (K-M Chen et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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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Synthesis and biological activity of isoprenoid bisphosphonates

Cited by 76 publications

References 19 publications

Inhibition of Geranylgeranyl Diphosphate Synthase Induces Apoptosis through Multiple Mechanisms and Displays Synergy with Inhibition of Other Isoprenoid Biosynthetic Enzymes

Inhibition of Geranylgeranyl Diphosphate Synthase Induces Apoptosis through Multiple Mechanisms and Displays Synergy with Inhibition of Other Isoprenoid Biosynthetic Enzymes

A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro

Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

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