Journal article
Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase
Molecular pharmacology, Vol.91(3), pp.229-236
03/2017
DOI: 10.1124/mol.116.107326
PMCID: PMC5325083
PMID: 28057800
Abstract
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.
Details
- Title: Subtitle
- Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase
- Creators
- Cheryl Allen - Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York (C.A.); Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania (S.K.); Penn State Cancer Institute, Hershey, Pennsylvania (H.T.); Department of Chemistry, University of Iowa, Iowa City, Iowa (R.A.M., J.I.M., D.F.W.); and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska (S.A.H.)Sandhya Kortagere - Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York (C.A.); Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania (S.K.); Penn State Cancer Institute, Hershey, Pennsylvania (H.T.); Department of Chemistry, University of Iowa, Iowa City, Iowa (R.A.M., J.I.M., D.F.W.); and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska (S.A.H.)Huaxiang Tong - Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York (C.A.); Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania (S.K.); Penn State Cancer Institute, Hershey, Pennsylvania (H.T.); Department of Chemistry, University of Iowa, Iowa City, Iowa (R.A.M., J.I.M., D.F.W.); and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska (S.A.H.)Robert A Matthiesen - Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York (C.A.); Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania (S.K.); Penn State Cancer Institute, Hershey, Pennsylvania (H.T.); Department of Chemistry, University of Iowa, Iowa City, Iowa (R.A.M., J.I.M., D.F.W.); and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska (S.A.H.)Joseph I Metzger - Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York (C.A.); Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania (S.K.); Penn State Cancer Institute, Hershey, Pennsylvania (H.T.); Department of Chemistry, University of Iowa, Iowa City, Iowa (R.A.M., J.I.M., D.F.W.); and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska (S.A.H.)David F Wiemer - Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York (C.A.); Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania (S.K.); Penn State Cancer Institute, Hershey, Pennsylvania (H.T.); Department of Chemistry, University of Iowa, Iowa City, Iowa (R.A.M., J.I.M., D.F.W.); and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska (S.A.H.)Sarah A Holstein - Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York (C.A.); Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania (S.K.); Penn State Cancer Institute, Hershey, Pennsylvania (H.T.); Department of Chemistry, University of Iowa, Iowa City, Iowa (R.A.M., J.I.M., D.F.W.); and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska (S.A.H.) sarah.holstein@unmc.edu
- Resource Type
- Journal article
- Publication Details
- Molecular pharmacology, Vol.91(3), pp.229-236
- DOI
- 10.1124/mol.116.107326
- PMID
- 28057800
- PMCID
- PMC5325083
- ISSN
- 0026-895X
- eISSN
- 1521-0111
- Grant note
- R01 CA172070 / NCI NIH HHS
- Language
- English
- Date published
- 03/2017
- Academic Unit
- Neuroscience and Pharmacology; Chemistry
- Record Identifier
- 9984216685502771
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