Abstract
The discovery of small molecules that selectively inhibit Mnks is considered of paramount importance towards deciphering the exact role of these proteins in carcinogenesis and to further validate them as anti-cancer drug targets. However, the dearth of structural information of Mnks is a major hurdle. This study unveils the 7H-pyrrolo[2,3-d]pyrimidine derivatives as potent inhibitors of Mnks. ATP and substrate competition assays showed that this scaffold interacts with the ATP binding site, but not with the substrate site. Screened against a panel of cancer cells, Mnk inhibitors were most potent against MV4-11 acute myeloid leukemia cells. The induction of apoptosis was shown to be mediated by downregulation of Mcl-1.
Keywords:
AML; CGP57380; Mnk kinase inhibitors; anti-cancer drug discovery; eIF4E phosphorylation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphatases / antagonists & inhibitors*
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Adenosine Triphosphatases / metabolism
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Cation Transport Proteins / antagonists & inhibitors*
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Cation Transport Proteins / metabolism
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Cell Cycle / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Copper-Transporting ATPases
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Humans
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Leukemia, Myeloid, Acute / pathology
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Molecular Structure
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Cation Transport Proteins
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Enzyme Inhibitors
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Adenosine Triphosphatases
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ATP7A protein, human
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Copper-Transporting ATPases