Discovery of potential covalent TYK2 inhibitors targeting Cys736 for the treatment of psoriasis.

TYK2 regulates the signaling of pro-inflammatory cytokines such as IL-12, IL-23, and type I interferons, which directly modulates immune cell activation and inflammatory responses, thereby has emerged as a promising therapeutic target for psoriasis. In this study, we identified Cys736 within the pseudokinase domain (JH2) of TYK2 as a potential covalent targeting site. Based on this, a series of covalent TYK2 inhibitors were designed and synthesized including aniline derivatives (A1 ∼ A7, B1 ∼ B5), benzylamine derivatives (C1 ∼ C2), and benzoic acid derivatives (D1 ∼ D6). Enzymatic activity assays and structure-activity relationship studies identified compound D3 as the most potent one, exhibiting in vitro inhibitory activity close to the positive control deucravacitinib. Molecular modeling provides preliminary indications that D3 may possess covalent inhibition potential targeting the Cys736 site. Flow cytometric analysis indicated that compound D3 effectively suppress the IFNα-mediated TYK2-STAT5 phosphorylation pathway. In an imiquimod induced mouse model of psoriasis, compound D3 significantly alleviated psoriatic symptoms, including erythema, scaling, and skin thickening, reduced the total Psoriasis Area and Severity Index (PASI) score, and effectively mitigated disease progression. Collectively, these results highlight compound D3 as a promising lead for the development of TYK2 JH2 inhibitors and offer new insights for the design of targeted covalent therapies against psoriasis.