目的 从中药天然产物数据库中发现具有新颖骨架靶向表皮生长因子受体（epidermal growth factor receptor，EGFR）治疗非小细胞肺癌（non-small cell lung cancer，NSCLC）的天然产物分子。方法 通过使用一致性虚拟筛选方法，从中药天然产物化合物库中筛选具有潜力的化合物分子，并进行酶活和细胞活性测试进行验证。结果 从由527个小分子组成的中药天然产物化合物库中筛选出了4个在实验中对EGFR有抑制活性的化合物分子，其中化合物异槲皮苷（248）对野生型NSCLC细胞的抑制活性（IC₅₀＝0.016 μmol/L）优于对照药剂吉非替尼（IC₅₀＝0.343 μmol/L），而化合物黄柏苷（376）不仅对野生型NSCLC细胞有抑制活性（IC₅₀＝18.725 μmol/L），并且对2种EGFR突变体细胞（L858R-T790M-C797S和del19-T790M-C797S）有2倍左右的选择性，具有一定的抗耐药潜力。结论 发现了4个对EGFR和NSCLC细胞有抑制活性的中药天然产物分子，为后续的结构改造和进一步得到更高效的EGFR小分子抑制剂提供参考，并为NSCLC药物的研发和临床研究奠定基础。

Objective To discover natural product molecules with novel scaffolds targeting the epidermal growth factor receptor (EGFR) for the treatment of non-small cell lung cancer (NSCLC) from a traditional Chinese medicine (TCM) natural product database. Methods A consensus virtual screening method was utilized to screen potential compound molecules from a TCM natural product compound library, followed by enzymatic and cellular activity tests for validation. Results A total of four compounds with inhibitory activity against EGFR were screened from a TCM natural product compound library consisting of 527 small molecules. Among them, the compound hirsutrin (248) exhibited superior inhibitory activity against wild-type NSCLC cells (IC₅₀= 0.016 μmol/L) compared to the control drug gefitinib (IC₅₀= 0.343 μmol/L). Additionally, the compound phellamurin (376) not only demonstrated inhibitory activity against wild-type NSCLC cells (IC₅₀= 18.725 μmol/L) but also showed approximately two-fold selectivity towards two EGFR mutant cells (L858R-T790M-C797S and del19-T790M-C797S), indicating potential anti-drug resistance properties. Conclusion Through this study, a total of four TCM natural product molecules with inhibitory activity against EGFR and NSCLC cells were identified. These findings will provide assistance for subsequent structural modifications and the development of more efficient small-molecule EGFR inhibitors, and lay a foundation for the research and clinical studies of NSCLC drugs.

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湖北省自然科学基金项目(2023AFB300,2024AFC030);湖北省教育厅科学研究计划重点项目(D20232103);湖北医药学院人才启动资金(2020QDJZR017);湖北医药学院药学院本科生科研训练计划项目(YSRTP202107)