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.