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

Abstract

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 <b>57</b>, a novel fourth-generation inhibitor to overcome EGFR^C797S-mediated resistance in patients harboring the activating EGFR^L858R mutation. <b>57</b> exhibits an improved potency compared to previous allosteric EGFR inhibitors. To our knowledge, <b>57</b> is the first allosteric EGFR inhibitor that demonstrates robust tumor regression in a mutant EGFR^L858R/C797S tumor model. Additionally, <b>57</b> 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 <b>57</b> 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.