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

作者：Xiaoxue Wang, Cheng Wang, Yakun Ma, Yongjun Piao, Yi Shi, Shuang Yang, Jia Li, Yan Fan · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c00693 · 被引用次数：4 · 研究领域：Protein Degradation and Inhibitors、Peptidase Inhibition and Analysis、Multiple Myeloma Research and Treatments

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 (DC 50 = 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.