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

Psoriasis is a chronic inflammatory skin disease closely related with T cells, and its management remains a challenge. Novel targets and associated drugs are urgently needed. Zeta-chain-associated protein kinase 70 kDa (ZAP-70) has been recognized as a potential target for treating autoimmune diseases due to its crucial role in T cell receptor signaling. In our previous work, we identified a potent and selective covalent ZAP-70 inhibitor with anti-inflammatory activity in vitro. Herein, we report the structural optimization of covalent ZAP-70 inhibitors. Our efforts led to the discovery of compound 25 (RDN2150), which exhibited potent inhibitory activity against ZAP-70 and favorable selectivity. It also demonstrated promising inhibitory effects on T cell activation and inflammatory cytokine production. Furthermore, a topical application of 25 resulted in significant efficacy in an imiquimod-induced psoriasis mouse model. Overall, these findings present the basis of a promising strategy for the treatment of psoriasis by targeting ZAP-70.银屑病（Psoriasis）是一种与T细胞密切相关的慢性炎症性皮肤病，其临床管理仍面临挑战，亟待开发新型治疗靶点及相关药物。Zeta链相关蛋白激酶70 kDa（ZAP-70）因在T细胞受体信号传导中发挥关键作用，已被认定为自身免疫性疾病的潜在治疗靶点。在既往研究中，我们已筛选出一种在体外具有抗炎活性的强效选择性共价ZAP-70抑制剂。本文报道了共价ZAP-70抑制剂的结构优化工作，最终获得化合物25（RDN2150）。该化合物对ZAP-70展现出强效抑制活性与良好的选择性，同时可有效抑制T细胞活化及炎症细胞因子的产生。进一步实验显示，局部施用化合物25可在咪喹莫特诱导的银屑病小鼠模型中取得显著治疗效果。综上，本研究为以ZAP-70为靶点治疗银屑病提供了极具前景的策略依据。