title: Insight into the Inhibition of Drug-Resistant Mutants of the Receptor Tyrosine Kinase EGFR.
abstract: Targeting acquired drug resistance represents the major challenge in the treatment of EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we describe the structure-based design, synthesis, and biological evaluation of a novel class of covalent EGFR inhibitors that exhibit excellent inhibition of EGFR-mutant drug-resistant cells. Protein X-ray crystallography combined with detailed kinetic studies led to a deeper understanding of the mode of inhibition of EGFR-T790M and provided insight into the key principles for effective inhibition of the recently discovered tertiary mutation at EGFR-C797S.
authors: Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 4a, 44227, Dortmund, Germany.
authors: Julian
authors: J
authors: Engel
authors: Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 4a, 44227, Dortmund, Germany.
authors: Christian
authors: C
authors: Becker
authors: Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 4a, 44227, Dortmund, Germany.
authors: Jonas
authors: J
authors: Lategahn
authors: Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 4a, 44227, Dortmund, Germany.
authors: Marina
authors: M
authors: Keul
authors: Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Hufelandstrasse 55, 45122, Essen, Germany.|German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
authors: Julia
authors: J
authors: Ketzer
authors: Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Hufelandstrasse 55, 45122, Essen, Germany.|German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
authors: Thomas
authors: T
authors: Mühlenberg
authors: Leibnitz-Institut für Analytische Wissenschaften-ISAS-e.V., Otto-Hahn-Strasse 6b, 44227, Dortmund, Germany.
authors: Laxmikanth
authors: L
authors: Kollipara
authors: Lead Discovery Center, Otto-Hahn-Strasse 15, 44227, Dortmund, Germany.
authors: Carsten
authors: C
authors: Schultz-Fademrecht
authors: Leibnitz-Institut für Analytische Wissenschaften-ISAS-e.V., Otto-Hahn-Strasse 6b, 44227, Dortmund, Germany.
authors: René P
authors: RP
authors: Zahedi
authors: Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Hufelandstrasse 55, 45122, Essen, Germany.|German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
authors: Sebastian
authors: S
authors: Bauer
authors: Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 4a, 44227, Dortmund, Germany. daniel.rauh@tu-dortmund.de.
authors: Daniel
authors: D
authors: Rauh
mesh_terms: D001665:Binding Sites; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D062105:Molecular Docking Simulation; D010766:Phosphorylation; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine; D066246:ErbB Receptors
keywords: cancer; drug discovery; drug resistance; medicinal chemistry; structure-based drug design