Abstract
Aim:
The EGFR inhibitors represent the first-line treatment of non-small-cell lung cancer. However, the emergence of resistance urgently requires the development of new inhibitors targeting drug-resistant mutants.
Methodology:
A recently released structure of an EGFR kinase domain in complex with an allosteric inhibitor and a mutant protein model derived from it were used to set up a low-cost high-throughput docking protocol for the fast identification of EGFR allosteric inhibitors.
Conclusion:
The virtual screening of commercially available compounds led to the identification of interesting new hit compounds. The most promising hit was confirmed to be a new allosteric inhibitor of wild-type and T790M/L858R double mutant EGFR which was able to inhibit the growth of non-small-cell lung cancer cell lines.
Keywords:
EGFR; allosteric inhibitors; high-throughput docking; protein kinases; virtual screening.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Allosteric Regulation / drug effects
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism
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Cell Line, Tumor
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Drug Discovery
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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High-Throughput Screening Assays / economics
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High-Throughput Screening Assays / methods
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Humans
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Molecular Docking Simulation / economics
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Molecular Docking Simulation / methods*
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Mutation
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology*
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Small Molecule Libraries / chemistry*
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Small Molecule Libraries / pharmacology*
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Small Molecule Libraries
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EGFR protein, human
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ErbB Receptors