Discovery and structural optimization of potent epidermal growth factor receptor (EGFR) inhibitors against L858R/T790M/C797S resistance mutation for lung cancer treatment.
Wang C, Wang X, Huang Z, Wang T, Nie Y, Yang S, Xiang R, Fan Y.
The C797S mutation in EGFR is a leading mechanism of clinically acquired resistance against osimertinib for non-small cell lung cancer (NSCLC). In this study, we identified a potent and oral EGFR<sup>L858R/T790M/C797S</sup> tyrosine kinase inhibitor, 14aj with a novel chemical scaffold. Compound 14aj showed low nanomolar activity against EGFR<sup>L858R/T790M/C797S</sup> mutant with IC<sub>50</sub> value as 0.010 μM. In vitro assays, compound 14aj exhibited high potency against NSCLC cells harboring EGFR<sup>L858R/T790M/C797S</sup> and induced tumor cell cycle arrest and cell apoptosis. 14aj inhibited cellular phosphorylation of EGFR. In vivo xenograft mouse model, oral administration of compound 14aj led to significant tumor regression without obvious toxicity. In addition, this compound showed good pharmacokinetics.