Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 6, Pages 2361-2372Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b01626
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Funding
- German Federal Ministry for Education and Research (NGFNPlus and e:Med) [BMBF 01GS08104, 01ZX1303C]
- Deutsche Forschungsgemeinschaft (DFG)
- European Union (European Regional Development Fund: Investing In Your Future) [EFRE-800400]
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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.
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