1. CHMFL-26 is a highly potent irreversible HER2 inhibitor for use in the treatment of HER2-positive and HER2-mutant cancers
- Author
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Jiang-yan Cao, Shuang Qi, Hong Wu, Ao-li Wang, Qing-wang Liu, Xi-xiang Li, Bei-lei Wang, Juan Ge, Feng-ming Zou, Cheng Chen, Jun-jie Wang, Chen Hu, Jing Liu, Wen-chao Wang, and Qing-song Liu
- Subjects
Pharmacology ,Receptor, ErbB-2 ,Breast Neoplasms ,General Medicine ,Xenograft Model Antitumor Assays ,Mice ,Drug Resistance, Neoplasm ,Cell Line, Tumor ,Mutation ,Animals ,Humans ,Pharmacology (medical) ,Female ,Cysteine ,Protein Kinase Inhibitors - Abstract
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.
- Published
- 2021