title: Lung Cancer: EGFR Inhibitors with Low Nanomolar Activity against a Therapy-Resistant L858R/T790M/C797S Mutant.
abstract: The treatment of non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) inhibitors is made challenging by acquired resistance caused by somatic mutations. Third-generation EGFR inhibitors have been designed to overcome resistance through covalent binding to the Cys 797 residue of the enzyme, and these inhibitors are effective against most clinically relevant EGFR mutants. However, the high dependence of these recent EGFR inhibitors on this particular interaction means that additional mutation of Cys 797 results in poor inhibitory activity, which leads to tumor relapse in initially responding patients. A new generation of irreversible and reversible mutant EGFR inhibitors was developed with strong noncovalent binding properties, and these compounds show high inhibitory activities against the cysteine-mutated L858R/T790M/C797S EGFR.
authors.affiliation: Eberhard Karls Universität Tübingen, Institute of Pharmaceutical Sciences, Pharmaceutical and Medicinal Chemistry, Auf der Morgenstelle 8, 72076, Tübingen, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Günther
authors.affiliation: Eberhard Karls Universität Tübingen, Institute of Pharmaceutical Sciences, Pharmaceutical and Medicinal Chemistry, Auf der Morgenstelle 8, 72076, Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Juchum
authors.affiliation: Cell Biology & Compound Screening Oncotest GmbH, Am Flughafen 12-14, 79108, Freiburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Kelter
authors.affiliation: Cell Biology & Compound Screening Oncotest GmbH, Am Flughafen 12-14, 79108, Freiburg, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Fiebig
authors.affiliation: Eberhard Karls Universität Tübingen, Institute of Pharmaceutical Sciences, Pharmaceutical and Medicinal Chemistry, Auf der Morgenstelle 8, 72076, Tübingen, Germany. stefan.laufer@uni-tuebingen.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Laufer
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D062105:Molecular Docking Simulation; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D017434:Protein Structure, Tertiary
chemical_list: D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors
keywords: EGFR; antitumor agents; drug design; inhibitors; kinases