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

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.