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Discovery and Structural Optimization of Covalent ZAP-70 Kinase Inhibitors against Psoriasis

文献类型：期刊论文

作者Rao, Danni1,2; Yang, Tao2,3; Feng, Huixu5; An, Qi5; Zhang, Shaofeng5; Yu, Jinghua6; Ren, Xuelian2,4; Diao, Xingxing2,6; Huang, He2,4,5; Tang, Wei2,3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-08-18
页码15
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c00606
通讯作者Tang, Wei(tangwei@simm.ac.cn) ; Xu, Shilin(slxu@simm.ac.cn)
英文摘要Psoriasis is a chronic inflammatory skin disease closelyrelatedwith T cells, and its management remains a challenge. Novel targetsand associated drugs are urgently needed. Zeta-chain-associated proteinkinase 70 kDa (ZAP-70) has been recognized as a potential target fortreating autoimmune diseases due to its crucial role in T cell receptorsignaling. In our previous work, we identified a potent and selectivecovalent ZAP-70 inhibitor with anti-inflammatory activity in vitro. Herein, we report the structural optimizationof covalent ZAP-70 inhibitors. Our efforts led to the discovery ofcompound 25 (RDN2150), which exhibited potent inhibitoryactivity against ZAP-70 and favorable selectivity. It also demonstratedpromising inhibitory effects on T cell activation and inflammatorycytokine production. Furthermore, a topical application of 25 resulted in significant efficacy in an imiquimod-induced psoriasismouse model. Overall, these findings present the basis of a promisingstrategy for the treatment of psoriasis by targeting ZAP-70.
WOS关键词THERAPY ; POTENT ; PATHOGENESIS ; INFLAMMATION ; INSIGHTS ; RECEPTOR ; BIOLOGY ; DESIGN ; CELLS
资助项目National Natural Science Foundation of China[82103973] ; Natural Science Foundation of Shanghai[20ZR1468400] ; Science and Technology Commission of Shanghai Municipality[20JC1418000]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001050815100001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/306941]  
专题中国科学院上海药物研究所
通讯作者Tang, Wei; Xu, Shilin
作者单位1.Chinese Acad Sci, Shanghai Inst, Dept Med Chem, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Antiinflammat & Immunopharmacol, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst, Ctr Chem Biol, Shanghai 201203, Peoples R China
5.Nanjing Univ, Sch Chinese Med, Chinese Mat Med, Nanjing 210023, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Metab & Pharmacokinet, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Rao, Danni,Yang, Tao,Feng, Huixu,et al. Discovery and Structural Optimization of Covalent ZAP-70 Kinase Inhibitors against Psoriasis[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023:15.
APA Rao, Danni.,Yang, Tao.,Feng, Huixu.,An, Qi.,Zhang, Shaofeng.,...&Xu, Shilin.(2023).Discovery and Structural Optimization of Covalent ZAP-70 Kinase Inhibitors against Psoriasis.JOURNAL OF MEDICINAL CHEMISTRY,15.
MLA Rao, Danni,et al."Discovery and Structural Optimization of Covalent ZAP-70 Kinase Inhibitors against Psoriasis".JOURNAL OF MEDICINAL CHEMISTRY (2023):15.

入库方式： OAI收割

来源：上海药物研究所

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