Author: An, Qi ; Huang, He ; Yu, Jinghua ; Xu, Shilin ; Ren, Xuelian ; Diao, Xingxing ; Tang, Wei ; Feng, Huixu ; Yang, Tao ; Rao, Danni ; Zhang, Shaofeng

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.

Journal of Medicinal Chemistry

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

Author: Huang, He ; Yang, Tao ; Zhang, Shaofeng ; Xu, Shilin ; An, Qi ; Yu, Jinghua ; Feng, Huixu ; Rao, Danni ; Tang, Wei ; Ren, Xuelian ; Diao, Xingxing

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 productionFurthermore, 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.

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Indication	Highest Phase	Country/Location	Organization	Date
Psoriasis	Preclinical	China	Chinese Academy of Sciences	18 Aug 2023

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