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 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 , a novel fourth-generation inhibitor to overcome EGFR-mediated resistance in patients harboring the activating EGFR mutation. exhibits an improved potency compared to previous allosteric EGFR inhibitors. To our knowledge, is the first allosteric EGFR inhibitor that demonstrates robust tumor regression in a mutant EGFR tumor model. Additionally, is active in an H1975 EGFR NSCLC xenograft model and shows superior efficacy in combination with osimertinib compared to the single agents. Our data highlight the potential of as a single agent against EGFR and EGFR and as combination therapy for EGFR- and EGFR-driven NSCLC.