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Indazole-Based Covalent Inhibitors To Target Drug-Resistant Epidermal Growth Factor Receptor

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posted on 22.02.2017 by Stefano Tomassi, Jonas Lategahn, Julian Engel, Marina Keul, Hannah L. Tumbrink, Julia Ketzer, Thomas Mühlenberg, Matthias Baumann, Carsten Schultz-Fademrecht, Sebastian Bauer, Daniel Rauh
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.