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Remodeling tumor-associated macrophage for anti-cancer effects by rational design of irreversible inhibition of mitogen-activated protein kinase-activated protein kinase 2

文献类型：期刊论文

作者Wang, Danyi1,2; Sun, Deqiao1,2; Wang, Xiaoyan2; Peng, Xia1,2; Ji, Yinchun1,2; Tang, Lu2,3; He, Qichang3; Chen, Danqi2,3; Yang, Ye1,2; Zhou, Xuan1,2
刊名MEDCOMM
出版日期2024-07-01
卷号5期号:7页码:e634
关键词anti-tumor irreversible inhibitor kinase macrophagemitogen-activated protein kinase-activated protein kinase 2 (MK2)
DOI10.1002/mco2.634
文献子类Article
英文摘要Mitogen-activated protein kinase-activated protein kinase 2 (MK2) emerges as a pivotal target in developing anti-cancer therapies. The limitations of ATP-competitive inhibitors, due to insufficient potency and selectivity, underscore the urgent need for a covalent irreversible MK2 inhibitor. Our initial analyses of The Cancer Genome Atlas database revealed MK2's overexpression across various cancer types, especially those characterized by inflammation, linking it to poor prognosis and highlighting its significance. Investigating MK2's kinase domain led to the identification of a unique cysteine residue, enabling the creation of targeted covalent inhibitors. Compound 11 was developed, demonstrating robust MK2 inhibition (IC50 = 2.3 nM) and high selectivity. It binds irreversibly to MK2, achieving prolonged signal suppression and reducing pathological inflammatory cytokines in macrophages. Furthermore, compound 11 or MK2 knockdown can inhibit the tumor-promoting macrophage M2 phenotype in vitro and in vivo. In macrophage-rich tumor model, compound 11 notably slowed growth in a dose-dependent manner. These findings support MK2 as a promising anticancer target, especially relevant in cancers fueled by inflammation or dominated by macrophages, and provide compound 11 serving as an invaluable chemical tool for exploring MK2's functions.Through rational design covalent MK2 inhibitors targeting the unique cysteine residue, we discovered that compound 11 exhibited potent prolonged MK2 activity inhibition, high kinase selectivity, and favorable in vivo anti-tumor efficacy image .
WOS关键词DOUBLE-BLIND ; MK2 ; P38 ; CANCER ; SAFETY ; PHARMACODYNAMICS ; PHOSPHORYLATION ; EFFICACY
WOS研究方向Research & Experimental Medicine
语种英语
WOS记录号WOS:001268173300001
出版者WILEY
源URL[http://119.78.100.183/handle/2S10ELR8/317014]  
专题新药研究国家重点实验室
通讯作者Xiong, Bing; Ai, Jing
作者单位1.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai, Peoples R China
2.Univ Chinese Acad Sci, Sch Pharm, Beijing, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai, Peoples R China
4.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Danyi,Sun, Deqiao,Wang, Xiaoyan,et al. Remodeling tumor-associated macrophage for anti-cancer effects by rational design of irreversible inhibition of mitogen-activated protein kinase-activated protein kinase 2[J]. MEDCOMM,2024,5(7):e634.
APA Wang, Danyi.,Sun, Deqiao.,Wang, Xiaoyan.,Peng, Xia.,Ji, Yinchun.,...&Ai, Jing.(2024).Remodeling tumor-associated macrophage for anti-cancer effects by rational design of irreversible inhibition of mitogen-activated protein kinase-activated protein kinase 2.MEDCOMM,5(7),e634.
MLA Wang, Danyi,et al."Remodeling tumor-associated macrophage for anti-cancer effects by rational design of irreversible inhibition of mitogen-activated protein kinase-activated protein kinase 2".MEDCOMM 5.7(2024):e634.

入库方式： OAI收割

来源：上海药物研究所

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