Discovery of Potent EGFR Inhibitors for Del19 and L858R/T790M Mutants Through Structure‐Based Virtual Screening and Biological Evaluation

Abstract

ABSTRACT Epidermal growth factor receptor (EGFR) mutation‐mediated drug resistance represents a major clinical challenge in the treatment of non‐small cell lung cancer (NSCLC). In this study, the lead compound XJ2‐2 was identified through structure‐based virtual screening. It exhibited potent anti‐proliferative activity against both EGFRDel19 mutant PC‐9 cells and EGFRL858R/T790M mutant H1975 cells, with IC50 values of 0.88 ± 0.12 μM and 0.77 ± 0.09 μM, respectively. Mechanistic studies have demonstrated that XJ2‐2 directly targets and binds to the EGFR, thereby effectively inhibiting EGFR phosphorylation and its downstream signaling pathways in both in vitro and in vivo models. In tumor‐bearing mouse models, XJ2‐2 significantly reduced tumor burden. Preclinical safety evaluation indicated that no treatment‐related toxicity was observed for XJ2‐2 at all tested doses. With its novel molecular scaffold and mutant‐selective inhibitory profile, XJ2‐2 represents a promising lead compound for overcoming NSCLC drug resistance and advancing the development of next‐generation EGFR inhibitors.