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

Abstract

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.

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“…The pseudo-first order reaction rate of glutathione (GSH) addition was a common method to profile the reactivity and selectivity of covalent inhibitors containing the acrylamide moiety. − In order to determine the covalent characters of 56 , its pseudo-first order reaction rate of GSH addition was determined and is summarized in Table and Figures S5–S7 (Supporting Information), where FDA-approved covalent drugs afatinib and osimertinib were included as positive controls. 56 has a reaction K pseudo first value of 2.75 ± 0.49 × 10 –3 min –1 , while those of afatinib and osimertinib are >10-fold greater, indicating that 56 reacted GSH 10-fold slower than afatinib and osimertinib did.…”

“…S13 was converted into the mesylate S14, which underwent a Scheme 3. Synthesis of Final Compounds 32,33,[37][38][39][40]42, The synthetic routes of 41 and 43−54 are summarized in Scheme 5. Reductive amination of S3 and 1-Boc piperazine yielded 41a, which was subjected to aqueous sodium carbonate to remove the Troc group and a subsequent Suzuki coupling reaction, furnishing 41b.…”

“…The residue was redissolved in dichloromethane (4 mL), TFA (2 mL) was added, and the mixture was stirred for additional 1 h at room temperature before concentration in vacuo and purification by HPLC to afford a TFA salt of 41 (41 mg, 46%) as a white solid. 1 (42,LJA063). To a solution of 8a (13 mg, 0.03 mmol) and Et 3 N (8 mg, 0.08 mmol) in anhydrous dichloromethane (5 mL), acryloyl chloride (2 mg, 0.03 mmol) was added, and the mixture was stirred at room temperature for 1 h before concentration in vacuo and purification by HPLC to afford a TFA salt of 42 (11 mg, 80%) as white solid.…”

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“…Similarly, inhibiting the protein product of ZAP70, which is also essential for T-cell signaling, has demonstrated anti-in ammatory properties in vitro and effectiveness in treating psoriasis in mice. 30 Given its similar pathway and risk reduction pro le, ZAP70 also emerges as a candidate for further research in the context of managing autoimmune diseases.…”