Trisubstituted Pyridinylimidazoles as Potent Inhibitors of the Clinically Resistant L858R/T790M/C797S EGFR Mutant: Targeting of Both Hydrophobic Regions and the Phosphate Binding Site

Inhibition
of the epidermal growth factor receptor represents one
of the most promising strategies in the treatment of lung cancer.
Acquired resistance compromises the clinical efficacy of EGFR inhibitors
during long-term treatment. The recently discovered EGFR-C797S mutation
causes resistance against third-generation EGFR inhibitors. Here we
present a rational approach based on extending the inhibition profile
of a p38 MAP kinase inhibitor toward mutant EGFR inhibition. We used
a privileged scaffold with proven cellular potency as well as in vivo
efficacy and low toxicity. Guided by molecular modeling, we synthesized
and studied the structure–activity relationship of 40 compounds
against clinically relevant EGFR mutants. We successfully improved
the cellular EGFR inhibition down to the low nanomolar range with
covalently binding inhibitors against a gefitinib resistant T790M
mutant cell line. We identified additional noncovalent interactions,
which allowed us to develop metabolically stable inhibitors with high
activities against the osimertinib resistant L858R/T790M/C797S mutant.