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
  • 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.
Products