A new motif for inhibitors of geranylgeranyl diphosphate synthase

Foust, Benjamin J.; Allen, Cheryl; Holstein, Sarah A.; Wiemer, David F.

doi:10.1016/j.bmc.2016.06.019

Cited by 15 publications

(15 citation statements)

References 22 publications

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“…Not only has our work demonstrated potential for GGDPS inhibitors as antimyeloma agents (Holstein and Hohl, 2011;Zhou et al, 2014a;Dykstra et al, 2015), but there has also been interest in the use of GGDPS inhibitors as anticancer agents for solid tumors models (Reilly et al, 2016) and in nonmalignant conditions such as pulmonary fibrosis (Osborn-Heaford et al, 2015). Previous efforts to develop GGDPS inhibitors have focused in large part on branched compounds, including V-shaped inhibitors such as DGBP and its analogs as well as more recently U-shaped inhibitors (Wiemer et al, 2007;K-M Chen et al, 2008;Barney et al, 2010;Zhou et al, 2014b;Foust et al, 2016). Prior crystallography studies demonstrated that the V-shaped compounds can occupy both the FDP and the GGDP sites (K- M Chen et al, 2008).…”

Section: Discussionmentioning

confidence: 89%

“…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). Subsequent efforts focused on modifications of the V-shaped motif (K-M Chen et al, 2008;Barney et al, 2010;Zhou et al, 2014b;Foust et al, 2016). More recently, a series of triazole bisphosphonates were prepared and it was determined that a mixture of geranyl and neryl triazole bisphosphonates (Fig.…”

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: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

et al. 2017

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“…We already have demonstrated that the Rap1a and ELISA assays give concordant results for GGDPS inhibitors. 9,10,12,29 The HMG-CoA reductase inhibitor lovastatin, which inhibits the synthesis of mevalonate and therefore depletes cells of all isoprenoids downstream of mevalonate, was used as a positive control in these studies. 6 Of the three compounds examined, the bishomoneryl compound 17c most potently disrupted protein geranylgeranylation, with activity seen at a concentration as low as 0.5 μM.…”

Section: Biological Results and Discussionmentioning

confidence: 99%

Bishomoisoprenoid triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase

Wills

Metzger

Allen

et al. 2017

Bioorganic & Medicinal Chemistry

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Protein geranylgeranylation reactions are dependent on the availability of geranylgeranyl diphosphate (GGDP), which serves as the isoprenoid donor. Inhibition of GGDP synthase (GGDPS) is of interest from a drug development perspective as GGDPS inhibition results in impaired protein geranylgeranylation, which in multiple myeloma, disrupts monoclonal protein trafficking and induces apoptosis. We have recently reported on a series of isoprenoid triazole bisphosphonates and have demonstrated that a 3:1 mixture of homogeranyl and homoneryl isomers potently, and in a synergistic manner, inhibits GGDPS. We now present the synthesis and biological evaluation of a novel series of bishomoisoprenoid triazoles which furthers our understanding of the structure-function relationship of this class. These studies demonstrate the importance of chain length and olefin stereochemistry on inhibitory activity.

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“…4 Several other dialkyl bisphosphonates have been reported to show comparable activity, 5,6 and similar activity has been found more recently in the closely related ether 4 . 7 While further improvements on the V-shaped motif of these compounds may yet be possible, 8 in our recent efforts 9,10 to secure more potent inhibitors we have examined bisphosphonates assembled through click chemistry. 11,12 In this vein, the most potent inhibitor we have identified to date is the bisphosphonate 5 .…”

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confidence: 99%