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

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

  • Acta Pharmacol Sin. 2022 Oct;43(10):2678-2686. doi: 10.1038/s41401-022-00882-x.
Jiang-Yan Cao  # 1 2,  Shuang Qi  # 1 3,  Hong Wu  # 1 3,  Ao-Li Wang 1 3,  Qing-Wang Liu 1 3,  Xi-Xiang Li 1 3,  Bei-Lei Wang 1 3,  Juan Ge 1 2,  Feng-Ming Zou 1 3,  Cheng Chen 1,  Jun-Jie Wang 1 2,  Chen Hu 1 3,  Jing Liu 4 5,  Wen-Chao Wang 6 7,  Qing-Song Liu 8 9 10 11
Affiliations

Affiliations

  • 1 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.
  • 2 University of Science and Technology of China, Hefei, 230026, China.
  • 3 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China.
  • 4 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China. [email protected].
  • 5 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China. [email protected].
  • 6 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China. [email protected].
  • 7 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China. [email protected].
  • 8 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China. [email protected].
  • 9 University of Science and Technology of China, Hefei, 230026, China. [email protected].
  • 10 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China. [email protected].
  • 11 Precision Medicine Research Laboratory of Anhui Province, Hefei, 230088, China. [email protected].
  • # Contributed equally.
PMID: 35228653 DOI: 10.1038/s41401-022-00882-x
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.

Keywords

HER2; breast cancers; drug resistance; gastric cancers; irreversible inhibitor.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16069
    99.82%, HER2 Inhibitor