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

doi:10.1038/s41401-022-00882-x

	CHMFL-26 is a highly potent irreversible HER2 inhibitor for use in the treatment of HER2-positive and HER2-mutant cancers
	Cao, Jiang-yan 1,2; Qi, Shuang 1,3; Wu, Hong 1,3; Wang, Ao-li 1,3; Liu, Qing-wang 1,3; Li, Xi-xiang 1,3; Wang, Bei-lei 1,3; Ge, Juan 1,2; Zou, Feng-ming 1,3; Chen, Cheng 1
刊名	ACTA PHARMACOLOGICA SINICA
	2022-02-28
关键词	HER2 breast cancers gastric cancers irreversible inhibitor drug resistance
ISSN号	1671-4083
DOI	10.1038/s41401-022-00882-x
通讯作者	Liu, Jing(jingliu@hmfl.ac.cn) ; Wang, Wen-chao(wwcbox@hmfl.ac.cn) ; Liu, Qing-song(qsliu97@hmfl.ac.cn)
英文摘要	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.
资助项目	National Natural Science Foundation of China[81903659] ; National Natural Science Foundation of China[81872748] ; National Natural Science Foundation of China[81903650] ; Plan for Major Anhui Provincial Science and Technology Project[202003a07020006] ; Natural Science Foundation of Anhui Province[1908085MH259] ; Natural Science Foundation of Anhui Province[2108085QH377] ; Natural Science Foundation of Anhui Province[2008085MH274] ; China Postdoctoral Science Foundation[2020M671916] ; Frontier Science Key Research Program of CAS[QYZDB-SSW-SLH037] ; Collaborative Innovation Program of Hefei Science Center, CAS[2020HSC-CIP009] ; CASHIPS Director's Fund[YZJJZX202011] ; CASHIPS Director's Fund[BJPY2019A03] ; CASHIPS Director's Fund[YZJJ2021QN38] ; Youth Innovation Promotion Association of CAS[2019437] ; High Magnetic Field Laboratory of Anhui Province
WOS关键词	TRASTUZUMAB EMTANSINE T-DM1 ; BREAST-CANCER ; PLUS VINORELBINE ; TYROSINE KINASE ; LAPATINIB ; SAFETY ; RESISTANCE ; MUTATIONS ; NERATINIB ; THERAPY
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBL GROUP
WOS记录号	WOS:000762159200002
资助机构	National Natural Science Foundation of China ; Plan for Major Anhui Provincial Science and Technology Project ; Natural Science Foundation of Anhui Province ; China Postdoctoral Science Foundation ; Frontier Science Key Research Program of CAS ; Collaborative Innovation Program of Hefei Science Center, CAS ; CASHIPS Director's Fund ; Youth Innovation Promotion Association of CAS ; High Magnetic Field Laboratory of Anhui Province
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/127793]
专题	中国科学院合肥物质科学研究院
通讯作者	Liu, Jing; Wang, Wen-chao; Liu, Qing-song
作者单位	1.Chinese Acad Sci, Inst Hlth & Med Technol, Hefei Inst Phys Sci, Anhui Prov Key Lab Med Phys & Technol, Hefei 230031, Peoples R China 2.Univ Sci & Technol China, Hefei 230026, Peoples R China 3.Chinese Acad Sci, Hefei Canc Hosp, Hefei 230031, Peoples R China 4.Precis Med Res Lab Anhui Prov, Hefei 230088, Peoples R China
推荐引用方式 GB/T 7714	Cao, Jiang-yan,Qi, Shuang,Wu, Hong,et al. CHMFL-26 is a highly potent irreversible HER2 inhibitor for use in the treatment of HER2-positive and HER2-mutant cancers[J]. ACTA PHARMACOLOGICA SINICA,2022.
APA	Cao, Jiang-yan.,Qi, Shuang.,Wu, Hong.,Wang, Ao-li.,Liu, Qing-wang.,...&Liu, Qing-song.(2022).CHMFL-26 is a highly potent irreversible HER2 inhibitor for use in the treatment of HER2-positive and HER2-mutant cancers.ACTA PHARMACOLOGICA SINICA.
MLA	Cao, Jiang-yan,et al."CHMFL-26 is a highly potent irreversible HER2 inhibitor for use in the treatment of HER2-positive and HER2-mutant cancers".ACTA PHARMACOLOGICA SINICA (2022).