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Design, synthesis and biological evaluation of indazole derivatives as selective covalent inhibitors of FGFR4 in wild-type and gatekeeper mutants

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资源类型：
Pubmed体系：
作者：
Yang Yingyue[1] ; He Xiaojie[1] ; Li Zulong[1] ; Ran Kai[2] ; Wang Ningyu[3] ; Zhao Lifeng[4] ; Liu Zhihao[1] ; Zeng Jun[1] ; Chang Bo[5] ; Feng Qiang[5] ; Zhang Qiangsheng[1] ; Yu Luoting[1] ;
机构： [1]Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. [2]College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing University of Arts and Sciences, Chongqing, 402160, China. [3]School of Life Science and Engineering, Southwest JiaoTong University, Chengdu, Sichuan, 611756, China. [4]Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, 610106, China. [5]College of Chemistry and Life Science, Chengdu Normal University, Chengdu, 611130, PR China.
出处：
DOI： 10.1016/j.ejmech.2023.115628
ISSN：

关键词： FGFR4 inhibitors Gatekeeper mutation Anti-cancer agents HCC

摘要：
Fibroblast growth factor receptor 4 (FGFR4) has been proved to be an effective target for cancer therapy. Aberration in FGF19/FGFR4 signaling is oncogenic driving force in human hepatocellular carcinoma (HCC). FGFR4 gatekeeper mutations induced acquired resistance remains an unmet clinical challenge for HCC treatment. In this study, a series of 1H-indazole derivatives were designed and synthesized as new irreversible inhibitors of wild-type and gatekeeper mutant FGFR4. These new derivatives showed significant FGFR4 inhibitory and antitumor activities, among which compound 27i was demonstrated to be the most potent compound (FGFR4 IC50 = 2.4 nM). Remarkably, compound 27i exhibited no activity against a panel of 381 kinases at 1 μM. Additionally, compound 27i displayed nanomolar IC50s against huh7 (IC50 = 21 nM) and two mutant cell lines, BaF3/ETV6-FGFR4-V550L and BaF3/ETV6-FGFR4-N535K (IC50 = 2.5/171 nM). Meanwhile, compound 27i exhibited potent antitumor potency (TGI: 83.0%, 40 mg/kg, BID) in Huh7 xenograft mouse models with no obvious toxicity observed. Overall, compound 27i was identified as a promising preclinical candidate for overcoming FGFR4 gatekeeper mutations for HCC treatment.Copyright © 2023 Elsevier Masson SAS. All rights reserved.

基金：
This work was supported by the National S&T Major Special Project on Major New Drug Innovations of China (2018ZX09201018) and the Sichuan Science and Technology Program (2023NSFSC0101).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2023]版：
大类 | 2 区 医学
小类 | 1 区 药物化学
最新[2023]版：
大类 | 2 区 医学
小类 | 1 区 药物化学
第一作者：
第一作者机构： [1]Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Yang Yingyue,He Xiaojie,Li Zulong,et al.Design, synthesis and biological evaluation of indazole derivatives as selective covalent inhibitors of FGFR4 in wild-type and gatekeeper mutants[J].European journal of medicinal chemistry.2023,258:115628.doi:10.1016/j.ejmech.2023.115628.
APA：
Yang Yingyue,He Xiaojie,Li Zulong,Ran Kai,Wang Ningyu...&Yu Luoting.(2023).Design, synthesis and biological evaluation of indazole derivatives as selective covalent inhibitors of FGFR4 in wild-type and gatekeeper mutants.European journal of medicinal chemistry,258,
MLA：
Yang Yingyue,et al."Design, synthesis and biological evaluation of indazole derivatives as selective covalent inhibitors of FGFR4 in wild-type and gatekeeper mutants".European journal of medicinal chemistry 258.(2023):115628

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