title: Indazole-Based Covalent Inhibitors To Target Drug-Resistant Epidermal Growth Factor Receptor.
abstract: The specific targeting of oncogenic mutant epidermal growth factor receptor (EGFR) is a breakthrough in targeted cancer therapy and marks a drastic change in the treatment of non-small cell lung cancer (NSCLC). The recurrent emergence of resistance to these targeted drugs requires the development of novel chemical entities that efficiently inhibit drug-resistant EGFR. Herein, we report the optimization process for a hit compound that has emerged from a phenotypic screen resulting in indazole-based compounds. These inhibitors are conformationally less flexible, target gatekeeper mutated drug-resistant EGFR-L858R/T790M, and covalently alkylate Cys797. Western blot analysis, as well as characterization of the binding kinetics and kinase selectivity profiling, substantiates our approach of targeting drug-resistant EGFR-L858R/T790M with inhibitors incorporating the indazole as hinge binder.
authors.affiliation: Faculty of Chemistry and Chemical Biology, TU Dortmund University , Otto-Hahn-Straße 4a, Dortmund D-44227, Germany.
authors.forename: Stefano
authors.initials: S
authors.lastname: Tomassi
authors.affiliation: Faculty of Chemistry and Chemical Biology, TU Dortmund University , Otto-Hahn-Straße 4a, Dortmund D-44227, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Lategahn
authors.affiliation: Faculty of Chemistry and Chemical Biology, TU Dortmund University , Otto-Hahn-Straße 4a, Dortmund D-44227, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Engel
authors.affiliation: Faculty of Chemistry and Chemical Biology, TU Dortmund University , Otto-Hahn-Straße 4a, Dortmund D-44227, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Keul
authors.affiliation: Faculty of Chemistry and Chemical Biology, TU Dortmund University , Otto-Hahn-Straße 4a, Dortmund D-44227, Germany.
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Tumbrink
authors.affiliation: Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen , Medical School, Hufelandstraße 55, Essen D-45122, Germany.|German Cancer Consortium (DKTK) , Heidelberg D-69120, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Ketzer
authors.affiliation: Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen , Medical School, Hufelandstraße 55, Essen D-45122, Germany.|German Cancer Consortium (DKTK) , Heidelberg D-69120, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mühlenberg
authors.affiliation: Lead Discovery Center GmbH , Otto-Hahn-Straße 15, Dortmund D-44227, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Baumann
authors.affiliation: Lead Discovery Center GmbH , Otto-Hahn-Straße 15, Dortmund D-44227, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz-Fademrecht
authors.affiliation: Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen , Medical School, Hufelandstraße 55, Essen D-45122, Germany.|German Cancer Consortium (DKTK) , Heidelberg D-69120, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bauer
authors.affiliation: Faculty of Chemistry and Chemical Biology, TU Dortmund University , Otto-Hahn-Straße 4a, Dortmund D-44227, Germany.
authors.forename: Daniel
authors.identifier: 0000-0002-1970-7642
authors.initials: D
authors.lastname: Rauh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D007191:Indazoles; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D062105:Molecular Docking Simulation; D009154:Mutation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors