Pivaloyloxymethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylation

Wiemer, Andrew J.; Yu, José S.; Shull, Larry W.; Barney, Rocky J.; Wasko, Brian M.; Lamb, Kimberly M.; Hohl, Raymond J.; Wiemer, David F.

doi:10.1016/j.bmc.2008.02.016

Cited by 53 publications

(57 citation statements)

References 32 publications

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“…Bisphosphonates are notorious for poor cellular entry due to their high charge-to-mass ratio, likely partially explaining the relatively high concentrations required in cell culture assays. Future studies could evaluate prodrug approaches that might confer liver targeting and mask the bisphosphonate negative charge, thus signifi cantly enhancing cellular entry (39)(40)(41).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Second, there is evidence that the high charge to mass ratio in salts of bisphosphonic acids at physiological pH can present some problem with transversing the cell membrane. 27 Aromatic bisphosphonates are more lipophilic than the lead compound digeranyl bisphosphonate (5), which may result in more facile drug delivery to the cell and relieve the need for use of a prodrug. 28 Third, bisphosphonates that contain isoprenoid olefin isomers display differing biological activity, but the potential isomerization or transposition of an alkene in vivo would be eliminated with an aromatic substructure.…”

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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“…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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Pivaloyloxymethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylation

Cited by 53 publications

References 32 publications

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

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

Synthesis and biological evaluation of a series of aromatic bisphosphonates

Geranylgeranyl diphosphate depletion inhibits breast cancer cell migration

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