Design, synthesis, and biological characterization of a hydrophobic tagging EGFR degrader for the treatment of non-small-cell lung cancer.

Abstract

EGFR is a validated therapeutic target for non-small cell lung cancer (NSCLC). Herein, we designed and synthesized a series of gefitinib-based hydrophobic tagging (Hyt) degraders to induce EGFR degradation. Among them, B3 was identified as an active degrader, with DC₅₀ values of 0.61 and 0.73 μM in the EGFR-del19 NSCLC cells HCC827 and PC9, respectively, and DT₅₀ values of 9.2 and 13.7 h. Mechanistic studies showed that B3 accelerated EGFR turnover and revealed a degradation process involving the ubiquitin-proteasome system and the autophagy-lysosome pathway. B3 also suppressed EGFR downstream signaling and inhibited the proliferation of HCC827 and PC9 cells, with IC₅₀ values of 0.17 and 0.25 μM, respectively. In an HCC827 xenograft model, B3 significantly inhibited tumor growth and reduced EGFR levels in tumor tissues without obvious toxicity. These results identify B3 as an active EGFR hydrophobic tag degrader and a useful compound for further investigation in NSCLC models harboring EGFR del19.