Abstract
We describe the design of a set of inhibitors to investigate the relationship between cyclin G associated kinase (GAK) and epidermal growth factor receptor (EGFR) in chordoma bone cancers. These compounds were characterized both in vitro and using in cell target engagement assays. The most potent chordoma inhibitors were further characterized in a kinome-wide screen demonstrating narrow spectrum profiles. While we observed a direct correlation between EGFR and antiproliferative effects on chordoma, GAK inhibition appeared to have only a limited effect.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminoquinolines / chemical synthesis
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Aminoquinolines / metabolism
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Aminoquinolines / pharmacology
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chordoma / drug therapy
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Drug Design
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / metabolism
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HEK293 Cells
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Intracellular Signaling Peptides and Proteins / metabolism
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Molecular Docking Simulation
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Protein Binding
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Quinazolines / chemical synthesis
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Quinazolines / metabolism
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Quinazolines / pharmacology
Substances
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Aminoquinolines
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Antineoplastic Agents
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Intracellular Signaling Peptides and Proteins
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Protein Kinase Inhibitors
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Quinazolines
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EGFR protein, human
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ErbB Receptors
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GAK protein, human
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Protein Serine-Threonine Kinases