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. jingliu@hmfl.ac.cn.
5 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China. jingliu@hmfl.ac.cn.
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. wwcbox@hmfl.ac.cn.
7 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China. wwcbox@hmfl.ac.cn.
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. qsliu97@hmfl.ac.cn.
9 University of Science and Technology of China, Hefei, 230026, China. qsliu97@hmfl.ac.cn.
10 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China. qsliu97@hmfl.ac.cn.
11 Precision Medicine Research Laboratory of Anhui Province, Hefei, 230088, China. qsliu97@hmfl.ac.cn.
# 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

Cat. No.

Product Name

Description

Target

Research Area
HY-16069

Tucatinib

99.82%, HER2 Inhibitor

EGFR

Cancer

Name
Email *

	Sorry, but the email address you supplied was invalid.