CHMFL-26 is a highly potent irreversible HER2 inhibitor for use in the treatment of HER2-positive and HER2-mutant cancers.

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.

• Authors: 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, Qing-Song Liu
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 43 Issue 10 Pg. 2678-2686 (Oct 2022) ISSN: 1745-7254 [Electronic] United States
• PMID: 35228653 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.

Chemical References

• Protein Kinase Inhibitors
• Receptor, ErbB-2
• Cysteine

Topics

• Animals
• Breast Neoplasms (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Cysteine
• Drug Resistance, Neoplasm
• Female
• Humans
• Mice
• Mutation
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Receptor, ErbB-2 (genetics, metabolism)
• Xenograft Model Antitumor Assays