Mono- and dialkyl isoprenoid bisphosphonates as geranylgeranyl diphosphate synthase inhibitors

Wiemer, Andrew J.; Yu, José S.; Lamb, Kimberly M.; Hohl, Raymond J.; Wiemer, David F.

doi:10.1016/j.bmc.2007.09.029

Cited by 45 publications

(54 citation statements)

References 27 publications

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“…Our laboratory has previously identified numerous mono-and dialkyl bisphosphonates as inhibitors of GGDPS, and many of these compounds also have been shown to decrease protein geranylgeranylation in cellular assays. 25 Based on our previous work, we hypothesized that the aromatic bisphosphonates synthesized would inhibit GGDPS. Compounds were first screened in vitro against recombinantly purified human GGDPS enzyme (Fig.…”

Section: Biological Results and Discussionmentioning

confidence: 99%

“…2) that selectively target geranylgeranyl diphosphate synthase (GGDPS, EC 2.5.1.29) over FDPS. 24,25,26 The enzyme GGDPS catalyzes elaboration of FPP (7) to GGPP (8), which is the required precursor for all protein geranylgeranylation. To explore further this class of compounds, aromatic analogs of mono-and digeranyl bisphosphonate (5) have been designed, synthesized, and assayed.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and biological evaluation of a series of aromatic bisphosphonates

Barney

Wasko

Dudakovic

et al. 2010

Bioorganic & Medicinal Chemistry

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Section: Biological Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of a series of aromatic bisphosphonates

Barney

Wasko

Dudakovic

et al. 2010

Bioorganic & Medicinal Chemistry

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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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“…We and our collaborators have developed bisphosphonate inhibitors of geranylgeranyl diphosphate synthase (GGDPS) [26][27][28][29][30]. GGDPS catalyzes the conversion of FPP to GGPP.…”

Section: Introductionmentioning

confidence: 99%

Geranylgeranyl diphosphate depletion inhibits breast cancer cell migration

2010

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The objective of this study was to determine whether geranylgeranyl diphosphate synthase inhibition, and therefore geranylgeranyl diphosphate depletion, interferes with breast cancer cell migration. Digeranyl bisphosphonate is a specific geranylgeranyl diphosphate synthase inhibitor. We demonstrate that digeranyl bisphosphonate depleted geranylgeranyl diphosphate and inhibited protein geranylgeranylation in MDA-MB-231 cells. Similar to GGTI-286, a GGTase I inhibitor, digeranyl bisphosphate significantly inhibited migration of MDA-MB-231 cells as measured by transwell assay. Similarly, digeranyl bisphosphonate reduced motility of MDA-MB-231 cells in a time-dependent manner as measured by large scale digital cell analysis system microscopy. Digeranyl bisphosphonate was mildly toxic and did not induce apoptosis. Treatment of MDA-MB-231 cells with digeranyl bisphosphonate decreased membrane while it increased cytosolic RhoA localization. In addition, digeranyl bisphosphonate increased RhoA GTP binding in MDA-MB-231 cells. The specificity of geranylgeranyl diphosphonate synthase inhibition by digeranyl bisphosphonate was confirmed by exogenous addition of geranylgeranyl diphosphate. Geranylgeranyl diphosphate addition prevented the effects of digeranyl bisphosphonate on migration, RhoA localization, and GTP binding to RhoA in MDA-MB-231 cells. These studies suggest that geranylgeranyl diphosphate synthase inhibitors are a novel approach to interfere with cancer cell migration.

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Mono- and dialkyl isoprenoid bisphosphonates as geranylgeranyl diphosphate synthase inhibitors

Cited by 45 publications

References 27 publications

Synthesis and biological evaluation of a series of aromatic bisphosphonates

Synthesis and biological evaluation of a series of aromatic bisphosphonates

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

Geranylgeranyl diphosphate depletion inhibits breast cancer cell migration

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