Abstract
An emerging method to help elucidate the mode of action of experimental drugs is to use untargeted metabolomics of cell-systems. The interpretations of such screens are however complex and more examples with inhibitors of known targets are needed. Here two T-cell lines were treated with an inhibitor of aspartate aminotransferase and analyzed with untargeted GC-MS. The interpretation of the data was enhanced by the use of two different cell-lines and supports aspartate aminotransferase as a target. In addition, the data suggest an unexpected off-target effect on glutamate decarboxylase. The results exemplify the potency of metabolomics to provide insight into both mode of action and off-target effects of drug candidates.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aspartate Aminotransferases / antagonists & inhibitors*
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Aspartate Aminotransferases / metabolism
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Drug Evaluation, Preclinical / methods
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Enzyme Inhibitors / pharmacology*
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Gas Chromatography-Mass Spectrometry
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Glutamate Decarboxylase / metabolism
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Humans
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Hydrazines / pharmacology*
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Jurkat Cells
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Metabolome / drug effects*
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Metabolomics
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Succinates / pharmacology*
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T-Lymphocytes / drug effects*
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T-Lymphocytes / metabolism
Substances
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Enzyme Inhibitors
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Hydrazines
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Succinates
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hydrazinosuccinic acid
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Aspartate Aminotransferases
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Glutamate Decarboxylase
Grants and funding
This study was funded by The Swedish Research Council, grant 350-2012-6611 (M.S.), and grant 2014-04495 (H.A), the Swedish Cancer Society, grant CAN 2016/741 (H.A.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.