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ASK120067 potently suppresses B-cell or T-cell malignancies in vitro and in vivo by inhibiting BTK and ITK

文献类型：期刊论文

作者Song, Peiran1,2; Bai, Gang2; Chan, Shingpan3; Zhang, Tao2; Tong, Linjiang2; Su, Yi2; Shen, Yanyan2; Chen, Yi2; Liu, Yingqiang2; Lai, Mengzhen2,4
刊名FRONTIERS IN PHARMACOLOGY
出版日期2022-12-15
卷号13页码:9
关键词Bruton's tyrosine kinase interleukin-2-inducible T cell kinase ASK120067 B-cell lymphoma T-cell leukemia
DOI10.3389/fphar.2022.1071114
通讯作者Ding, Jian(jding@simm.ac.cn) ; Xie, Hua(hxie@simm.ac.cn)
英文摘要Hyperactivation of Bruton's tyrosine kinase (BTK) or interleukin-2-inducible T cell kinase (ITK) has been attributed to the pathogenesis of B-cell lymphoma or T-cell leukemia, respectively, which suggests that Bruton's tyrosine kinase and interleukin-2-inducible T cell kinase are critical targets for the treatment of hematological malignancies. We identified a novel third-generation epidermal growth factor receptor (EGFR) inhibitor, ASK120067 (limertinib) in our previous research, which has been applied as a new drug application against non-small cell lung cancer in China. In this work, we found that ASK120067 displayed potent in vitro inhibitory efficacy against Bruton's tyrosine kinase protein and interleukin-2-inducible T cell kinase protein via covalent binding. In cell-based assays, ASK120067 dose-dependently suppressed Bruton's tyrosine kinase phosphorylation and exhibited anti-proliferation potency by inducing apoptosis in numerous B-lymphoma cells. Meanwhile, it caused growth arrest and induced the apoptosis of T-cell leukemia cells by attenuating interleukin-2-inducible T cell kinase activation. Oral administration of ASK120067 led to significant tumor regression in B-cell lymphoma and T-cell leukemia xenograft models by weakening Bruton's tyrosine kinase and interleukin-2-inducible T cell kinase signaling, respectively. Taken together, our studies demonstrated that ASK120067 exerted preclinical anti-tumor activities against B-/T-cell malignancy by targeting BTK/ITK.
WOS关键词IBRUTINIB
资助项目National Natural Science Foundation of China[81903638] ; National Natural Science Foundation of China[82273948] ; Lingang Laboratory Grant[LG202103-02-02] ; State Key Laboratory of Drug Research, and High-level new RD institute[SIMM2205KF-09] ; State Key Laboratory of Drug Research, and High-level new RD institute[2019B090904008] ; High-level Innovative Research Institute, Department of Science and Technology of Guangdong Province[2021B0909050003]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000905405900001
出版者FRONTIERS MEDIA SA
源URL[http://119.78.100.183/handle/2S10ELR8/304058]  
专题新药研究国家重点实验室
通讯作者Ding, Jian; Xie, Hua
作者单位1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai, Peoples R China
3.Jinan Univ, Coll Pharm, Guangzhou, Peoples R China
4.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai, Peoples R China
5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Hangzhou, Peoples R China
推荐引用方式
GB/T 7714		 Song, Peiran,Bai, Gang,Chan, Shingpan,et al. ASK120067 potently suppresses B-cell or T-cell malignancies in vitro and in vivo by inhibiting BTK and ITK[J]. FRONTIERS IN PHARMACOLOGY,2022,13:9.
APA Song, Peiran.,Bai, Gang.,Chan, Shingpan.,Zhang, Tao.,Tong, Linjiang.,...&Xie, Hua.(2022).ASK120067 potently suppresses B-cell or T-cell malignancies in vitro and in vivo by inhibiting BTK and ITK.FRONTIERS IN PHARMACOLOGY,13,9.
MLA Song, Peiran,et al."ASK120067 potently suppresses B-cell or T-cell malignancies in vitro and in vivo by inhibiting BTK and ITK".FRONTIERS IN PHARMACOLOGY 13(2022):9.

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来源：上海药物研究所

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