Abstract
Inactivation of the M2 form of pyruvate kinase (PKM2) in cancer cells is associated with increased tumorigenicity. To test the hypothesis that tumor growth may be inhibited through the PKM2 pathway, we generated a series of small-molecule PKM2 activators. The compounds exhibited low nanomolar activity in both biochemical and cell-based PKM2 activity assays. These compounds did not affect the growth of cancer cell lines under normal conditions in vitro, but strongly inhibited the proliferation of multiple lung cancer cell lines when serine was absent from the cell culture media. In addition, PKM2 activators inhibited the growth of an aggressive lung adenocarcinoma xenograft. These findings show that PKM2 activation by small molecules influences the growth of cancer cells in vitro and in vivo, and suggest that such compounds may augment cancer therapies.
MeSH terms
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Animals
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Benzylamines / chemistry
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Benzylamines / pharmacology*
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Carrier Proteins / agonists*
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Carrier Proteins / chemistry
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Carrier Proteins / metabolism
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Cell Line, Tumor
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Cell Survival / drug effects
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Enzyme Activation / drug effects
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Female
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Humans
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Lung Neoplasms / drug therapy
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Lung Neoplasms / metabolism*
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Lung Neoplasms / pathology*
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Membrane Proteins / agonists*
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Membrane Proteins / chemistry
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Membrane Proteins / metabolism
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Mice
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Models, Molecular
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Molecular Conformation
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Protein Binding
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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Thyroid Hormone-Binding Proteins
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Thyroid Hormones / agonists*
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Thyroid Hormones / chemistry
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Thyroid Hormones / metabolism
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Benzylamines
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Carrier Proteins
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Membrane Proteins
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Pyrazoles
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SGI-10067
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SGI-9380
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Thyroid Hormones