Discovery of Novel Allosteric EGFR L858R Inhibitors for the Treatment of Non-Small-Cell Lung Cancer as a Single Agent or in Combination with Osimertinib.

Addressing resistance to third-generation EGFR TKIs such as osimertinib via the EGFR C797S mutation remains a highly unmet need in EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we present the discovery of the allosteric EGFR inhibitor 57 , a novel fourth-generation inhibitor to overcome EGFR C797S -mediated resistance in patients harboring the activating EGFR L858R mutation. 57 exhibits an improved potency compared to previous allosteric EGFR inhibitors. To our knowledge, 57 is the first allosteric EGFR inhibitor that demonstrates robust tumor regression in a mutant EGFR L858R/C797S tumor model. Additionally, 57 is active in an H1975 EGFR L858R/T790M NSCLC xenograft model and shows superior efficacy in combination with osimertinib compared to the single agents. Our data highlight the potential of 57 as a single agent against EGFR L858R/C797S and EGFR L858R/T790M/C797S and as combination therapy for EGFR L858R - and EGFR L858R/T790M -driven NSCLC.