Discovery of Potent and Wild-Type-Sparing Fourth-Generation EGFR Inhibitors for Treatment of Osimertinib-Resistance NSCLC

Osimertinib resistance is an unmet clinical need for
the treatment
of non-small cell lung cancer (NSCLC), and the main mechanism is tertiary
C797S mutation of epidermal growth factor receptor (EGFR). To date,
there is no inhibitor approved for the treatment of Osimertinib-resistant
NSCLC. Herein, we reported a series of Osimertinib derivatives as
fourth-generation inhibitors which were rationally designed. Top candidate D51 potently inhibited the EGFRL858R/T790M/C797S mutant with an IC50 value of 14 nM and suppressed the
proliferation of H1975-TM cells with an IC50 value of 14
nM, which show over 500-fold selectivity against wild-type forms.
Moreover, D51 inhibited the EGFRdel19/T790M/C797S mutant and the proliferation of the PC9-TM cell line with IC50 values of 62 and 82 nM. D51 also exhibited
favorable in vivo druggability, including PK parameters, safety properties,
in vivo stability, and antitumor activity.