Discovery of Novel Fourth-Generation EGFR Inhibitors to Overcome C797S-Mediated Resistance.

Epidermal growth factor receptor (EGFR)-activating mutation is an important oncogenic driver of nonsmall cell lung cancer (NSCLC) patients. Osimertinib has been the first-line treatment for EGFR-mutated NSCLC. However, the tertiary C797S mutation leads to Osimertinib resistance by blocking the covalent binding of Cys797 to Osimertinib. To date, there are no approved inhibitors for the treatment of Osimertinib resistance. Herein, we identified a novel lead compound S8 targeting EGFR L858R/T790M/C797S by structure-based virtual screening and synthesized a series of novel compounds. Representative compound C34 showed potent inhibitory activity against EGFR L858R/T790M/C797S with an IC 50 of 5.1 nM and significantly inhibited the proliferation of the H1975-TM cell line harboring EGFR L858R/T790M/C797S with an IC 50 of 0.05 μM. Additionally, compound C34 demonstrated good pharmacokinetic properties with an oral bioavailability of 30.72% and significantly inhibited tumor growth in the H1975-TM xenograft tumor model. This study provides a novel thiazole derivative as an EGFR inhibitor to overcome C797S-mediated resistance.