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

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.