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

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.

Automated summary

This study identifies a potent and selective covalent ZAP-70 inhibitor with anti-inflammatory activity, which effectively inhibits T cell activation and inflammatory cytokine production. The topical application of this inhibitor also shows promising efficacy in a psoriasis mouse model.