Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
J Med Chem. 2023 Sep 14;66(17):12018-12032. doi: 10.1021/acs.jmedchem.3c00606. Epub 2023 Aug 18.
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 . Herein, we report the structural optimization of covalent ZAP-70 inhibitors. Our efforts led to the discovery of compound (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 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.
银屑病是一种与 T 细胞密切相关的慢性炎症性皮肤病，其治疗仍然是一个挑战。迫切需要新的靶点和相关药物。Zeta 链相关蛋白激酶 70kDa（ZAP-70）因其在 T 细胞受体信号转导中的关键作用，已被认为是治疗自身免疫性疾病的潜在靶点。在我们之前的工作中，我们发现了一种具有抗炎活性的强效和选择性的共价 ZAP-70 抑制剂。在此，我们报告了共价 ZAP-70 抑制剂的结构优化。我们的努力导致发现了化合物 (RDN2150)，它对 ZAP-70 表现出强大的抑制活性和良好的选择性。它还显示出对 T 细胞激活和炎症细胞因子产生的有希望的抑制作用。此外，局部应用 导致在咪喹莫特诱导的银屑病小鼠模型中具有显著疗效。总之，这些发现为通过靶向 ZAP-70 治疗银屑病提供了一种有前途的策略的基础。
