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 EGFRC797S 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 EGFRC797S-mediated resistance in patients harboring the activating EGFRL858R 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 EGFRL858R/C797S tumor
model. Additionally, 57 is active in an H1975 EGFRL858R/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 EGFRL858R/C797S and EGFRL858R/T790M/C797S and as combination therapy for EGFRL858R- and EGFRL858R/T790M-driven NSCLC.