Discovery of a Novel EGFR PROTAC Degrader against C797S Resistance Mutation with Potent Antitumor Efficacy in NSCLC Treatment

Abstract

C797S mutation is the predominant resistance mechanism for the third-generation EGFR inhibitor osimertinib in nonsmall cell lung cancer (NSCLC). To overcome this drug resistance, a novel class of EGFR^C797S PROTAC degraders was developed in human NSCLC models. 9ea was identified as the lead compound, demonstrating potent degradation of EGFR^C797S and other main EGFR mutants (DC₅₀ = 2.9 ± 1.1 nM, D_max = 93.1 ± 6.5%). It exhibited good selectivity for degradation over EGFR^WT. Additionally, 9ea induced cell cycle arrest and apoptosis. Mechanistic studies revealed that 9ea selectively induced EGFR^C797S degradation through a VHL and proteasome-dependent manner and downregulated EGFR-associated transcriptome. In NSCLC (EGFR^C797S) xenograft mouse models, 9ea significantly inhibited tumor growth (74.7% TGI @ 50 mg/kg) and effectively depleted EGFR proteins in tumor tissue. These findings suggest that 9ea is a potent and selective EGFR^C797S PROTAC degrader with potential for the treatment of EGFR mutant-driven NSCLC.