Targeted degradation of EGFR 19Del by PROTACs suppresses tumor growth in non-small-cell lung cancer.

Object: The occurrence of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) poses a significant challenge in treating non-small-cell lung cancer (NSCLC), limiting the clinical use of EGFR-TKIs. Proteolysis-targeting chimeras (PROTACs) demonstrate promise in preclinical settings. This study is aimed to design effective EGFR degraders by linking CRBN ligands with relatively lower molecular weights. Methods: Computational methods are employed to do the rational design for the PROTACs. Western blots are used to examine the expression of proteins including EGFR. Cell viability and colony-formation assays are conducted to evaluate the anti-proliferative effects of degraders to NSCLC cell lines, and apoptosis assays are assessed by Annexin V-FITC/PI dual staining followed by flow cytometry. Female BALB/c nude mice bearing HCC827 xenografts are administered compound 14 (30 mg/kg) by intraperitoneal injection and the tumor volume and weights are measured. Results: We designed and synthesized a series of highly potent degraders based on the first-generation EGFR-TKI gefitinib and a cereblon (CRBN) ligand. Among these degraders, compound 14, with a relatively low molecular weight of 814.32 Da, exhibits notable activity against EGFR Conclusion: With its low molecular weight and excellent in vitro and in vivo efficacy, compound 14 could serve as a promising lead for developing degrader-based therapies targeting mutated EGFR.