Abstract
Generating highly selective probes to interrogate protein kinase function in biological studies remains a challenge, and new strategies are required. Herein, we describe the development of the first highly selective and cell-permeable inhibitor of c-Src, a key signaling kinase in cancer. Our strategy involves extension of traditional inhibitor design by appending functionality proposed to interact with the phosphate-binding loop of c-Src. Using our selective inhibitor, we demonstrate that selective inhibition is significantly more efficacious than pan-kinase inhibition in slowing the growth of cancer cells. We also show that inhibition of c-Abl kinase, an off-target of most c-Src inhibitors, promotes oncogenic cell growth.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / chemistry
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Animals
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Antineoplastic Agents / pharmacology
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CSK Tyrosine-Protein Kinase
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Cell Line, Tumor
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Cell Proliferation
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Chemistry, Pharmaceutical / methods
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Drug Design
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Drug Screening Assays, Antitumor / methods
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Fibroblasts / cytology
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Humans
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Kinetics
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Mice
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Models, Chemical
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Neoplasms / drug therapy
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Neoplasms / metabolism
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Phosphates / chemistry
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Phosphorylation
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / chemistry
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Signal Transduction
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src-Family Kinases
Substances
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Antineoplastic Agents
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Phosphates
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Protein Kinase Inhibitors
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Adenosine Triphosphate
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Protein-Tyrosine Kinases
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CSK Tyrosine-Protein Kinase
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src-Family Kinases
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CSK protein, human