摘要Oncogene HER2 is amplified in 20％-25％of human breast cancers and 6.1％-23.0％of gastric cancers,and HER2-directed therapy significantly improves the outcome for patients with HER2-positive cancers.However,drug resistance is still a clinical challenge due to primary or acquired mutations and drug-induced negative regulatory feedback.In this study,we discovered a potent irreversible HER2 kinase inhibitor,CHMFL-26,which covalently targeted cysteine 805 of HER2 and effectively overcame the drug resistance caused by HER2 V777L,HER2 L755S,HER2 exon 20 insertions,and p95-HER2 truncation mutations.CHMFL-26 displayed potent antiproliferation efficacy against HER2-amplified and mutant cells through constant HER2-mediated signaling pathway inhibition and apoptosis induction.In addition,CHMFL-26 suppressed tumor growth in a dose-dependent manner in xenograft mouse models.Together,these results suggest that CHMFL-26 may be a potential novel anti-HER2 agent for overcoming drug resistance in HER2-positive cancer therapy.