Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, #555 Zu Chong Zhi Road, Shanghai, 201203, China; University of Chinese Academy of Science, 19 Yuquan Road, Beijing, 110039, China.
Laboratory of Anti-inflammation and Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Eur J Med Chem. 2021 Jul 5;219:113393. doi: 10.1016/j.ejmech.2021.113393. Epub 2021 Mar 30.
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.
ZAP-70（zeta 链相关蛋白激酶 70 kDa）信号通路及其功能已涉及 T 细胞的发育和适应性免疫信号转导。因此，它是自身免疫性疾病的一个很有前途的靶点。尽管已经开发出了可逆的 ZAP-70 激酶结构域抑制剂，但它们要么作用较弱，要么选择性不强。我们在此报告了基于结构的 ZAP-70 激酶结构域的首个强效和共价抑制剂的开发。特别是，化合物 18（RDN009）对 ZAP-70 具有良好的选择性，相对于结构相关的 Syk 激酶，显示出对 T 细胞增殖、活化和炎症细胞因子产生的有效抑制作用。质谱分析进一步证实了抑制剂与 ZAP-70 蛋白在 C346 位的共价结合。总的来说，共价抑制剂 RDN009 是 ZAP-70 的一种有效且选择性的探针，可进一步开发用于治疗自身免疫性疾病。
