期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 219, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113393
关键词
Zeta-chain associated protein kinase 70 kDa (ZAP-70); Covalent inhibitor; T cell; Autoimmune diseases
资金
- Natural Science Foundation of Shanghai [20ZR1468400]
- Science & Technology Commission of Shanghai Municipality, China [18431907100]
- Young Elite Scientists Sponsorship Program by CAST [2019-2021QNRC001]
- National Natural Science Foundation of China [81973164]
- Shanghai Pujiang Program [19PJ1411200]
- Shanghai Institute of Materia Medica
ZAP-70 signaling pathway is crucial in T cell development and immune response, making it a promising target for autoimmune disease treatment. The development of a selective and potent covalent inhibitor of ZAP-70 kinase domain shows promising inhibitory effects on T cell activation and inflammatory response.
ZAP-70 (zeta-chain associated protein kinase 70 kDa) signaling pathway and its functions have been involved in the development and adaptive immune signaling of T cell. It thus represents a promising target for autoimmune diseases. Although reversible ZAP-70 kinase domain inhibitors have been developed, they are either weak or nonselective. We report herein the structure-guided development of the first potent and covalent inhibitor of ZAP-70 kinase domain. In particular, compound 18 (RDN009) showed good selectivity for ZAP-70 over structurally related Syk, and displayed potent inhibitory effects on T cell proliferation, activation, and inflammatory cytokine production. A mass spectrometry analysis further confirmed the covalent linkage between the inhibitor and ZAP-70 protein at C346. Overall, the covalent inhibitor RDN009 represents a potent and selective probe of ZAP-70 for further development for treatment of autoimmune diseases. (C) 2021 Elsevier Masson SAS. All rights reserved.
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