Discovery of potent CRBN-recruiting epidermal growth factor receptor (EGFR) degraders in vitro.

Epidermal Growth Factor Receptor (EGFR), a transmembrane receptor tyrosine kinase (RTK) belonging to the ErbB family, initiates cancer-promoting pathways upon binding with epidermal growth factor (EGF). This activation leads to increased cellular proliferation, inhibition of apoptosis, invasion, and neovascularization. EGFR plays a critical role in non-small cell lung cancer (NSCLC) and is targeted by EGFR tyrosine kinase inhibitors (TKIs). However, resistance to these inhibitors often develops over time, complicating treatment strategies. Proteolysis-targeting chimeras (PROTACs) represent a novel class of drugs that induce targeted protein degradation by promoting ubiquitination upon binding, resulting in degradation via the 26S proteasome. This innovative strategy potentially addresses the drug resistance associated with small molecule inhibitors and holds promise for the treatment of NSCLC. In this paper, we designed and synthesized a series of small molecule PROTACs targeting EGFR utilizing WZ4002, known for its mutation selectivity, as the warhead. These compounds were evaluated for their antiproliferative activity against A549 and NCl-H1975 cell lines, with WZ4002 serving as a control drug. Most compounds exhibited moderate to strong activity against NCl-H1975 cells, with comparatively weaker effects on A549 cells. Among the tested compounds, HJM- 17 and HJM- 19 emerged as the most potent against NCl-H1975 cells. Further analysis through protein immunoblotting revealed that HJM- 17 effectively reduced the expression of EGFR^L858R/T790M. These active compounds lay the groundwork for future studies focused on EGFR-targeting PROTACs.