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Discovery of a Covalent Inhibitor Selectively Targeting the Autophosphorylation Site of c-Src Kinase

文献类型：期刊论文

作者Zhang, Huimin6,7; Xu, Dounan5,6,7; Huang, Hongchan3,4; Jiang, Hao6; Hu, Linghao7; Liu, Liping3,6; Sun, Ge3,6; Gao, Jing3,6; Li, Yuanqing2,3,6; Xia, Cuicui1
刊名ACS CHEMICAL BIOLOGY
出版日期2024-03-21
页码12
ISSN号1554-8929
DOI10.1021/acschembio.4c00048
通讯作者Kong, Xiangqian(kong_xiangqian@gibh.ac.cn) ; Wang, Mingliang(wangmingliang@simm.ac.cn) ; Luo, Cheng(cluo@simm.ac.cn)
英文摘要Nonreceptor tyrosine kinase c-Src plays a crucial role in cell signaling and contributes to tumor progression. However, the development of selective c-Src inhibitors turns out to be challenging. In our previous study, we performed posttranslational modification-inspired drug design (PTMI-DD) to provide a plausible way for designing selective kinase inhibitors. In this study, after identifying a unique pocket comprising a less conserved cysteine and an autophosphorylation site in c-Src as well as a promiscuous covalent inhibitor, chemical optimization was performed to obtain (R)-LW-Srci-8 with nearly 75-fold improved potency (IC50 = 35.83 +/- 7.21 nM). Crystallographic studies revealed the critical C-FC & boxH;O interactions that may contribute to tight binding. The k(inact) and K-i values validated the improved binding affinity and decreased warhead reactivity of (R)-LW-Srci-8 for c-Src. Notably, in vitro tyrosine kinase profiling and cellular activity-based protein profiling (ABPP) cooperatively indicated a specific inhibition of c-Src by (R)-LW-Srci-8. Intriguingly, (R)-LW-Srci-8 preferentially binds to inactive c-Src with unphosphorylated Y419 both in vitro and in cells, subsequently disrupting the autophosphorylation. Collectively, our study demonstrated the feasibility of developing selective kinase inhibitors by cotargeting a nucleophilic residue and a posttranslational modification site and providing a chemical probe for c-Src functional studies.
WOS关键词ORTHOGONAL MULTIPOLAR INTERACTIONS ; CHRONIC MYELOID-LEUKEMIA ; TYROSINE KINASE ; PROTEIN-KINASE ; BREAST-CANCER ; ACTIVATION ; REACTIVITY ; CHEMISTRY ; MECHANISM ; FLUORINE
资助项目National Natural Science Foundation of China ; National Centre for Protein Science Shanghai (Shanghai Science Research Center, Protein Expression and Purification system)[2022YFC3400500] ; National Centre for Protein Science Shanghai (Shanghai Science Research Center, Protein Expression and Purification system)[2021ZD0203900] ; National Key R&D Program of China[81821005] ; National Key R&D Program of China[92253303] ; National Key R&D Program of China[22377089] ; National Natural Science Foundation of China ; National Multidisciplinary Innovation Team of Traditional Chinese Medicine[ZYYCXTD-202004] ; National Administration of Traditional Chinese Medicine[2019B090904008] ; High-level new RD institute[2021B0909050003] ; High-level Innovative Research Institute ; Department of Science and Technology of Guangdong Province[22107101] ; Natural Science Foundation of China[2021B1515420002] ; Guangdong Basic and Applied Basic Research Foundation[2021QN02Y734] ; Pearl River Talents Plan
WOS研究方向Biochemistry & Molecular Biology
语种英语
WOS记录号WOS:001189801900001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/310342]  
专题新药研究国家重点实验室
通讯作者Kong, Xiangqian; Wang, Mingliang; Luo, Cheng
作者单位1.Univ Sci & Technol China, Div Life Sci & Med, Hefei 230026, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
3.Univ Chinese Acad Sci UCAS, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Ctr Chem Biol & Drug Discovery, State Key Lab Resp Dis, Guangzhou Inst Biomed & Hlth, Guangzhou 510530, Peoples R China
5.Shanghai Univ, Coll Sci, Dept Chem, Shanghai 200444, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
7.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528437, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Huimin,Xu, Dounan,Huang, Hongchan,et al. Discovery of a Covalent Inhibitor Selectively Targeting the Autophosphorylation Site of c-Src Kinase[J]. ACS CHEMICAL BIOLOGY,2024:12.
APA Zhang, Huimin.,Xu, Dounan.,Huang, Hongchan.,Jiang, Hao.,Hu, Linghao.,...&Luo, Cheng.(2024).Discovery of a Covalent Inhibitor Selectively Targeting the Autophosphorylation Site of c-Src Kinase.ACS CHEMICAL BIOLOGY,12.
MLA Zhang, Huimin,et al."Discovery of a Covalent Inhibitor Selectively Targeting the Autophosphorylation Site of c-Src Kinase".ACS CHEMICAL BIOLOGY (2024):12.

入库方式： OAI收割

来源：上海药物研究所

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