A novel highly selective allosteric inhibitor of tyrosine kinase 2 (TYK2) can block inflammation- and autoimmune-related pathways
Background
Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family, which also includes JAK1, JAK2, and JAK3. TYK2 plays a pivotal role in signal transduction and immune regulation and is implicated in the pathogenesis of various inflammatory and autoimmune diseases, such as psoriasis and systemic lupus erythematosus (SLE). As a result, TYK2 is an attractive therapeutic target. Achieving selective inhibition of TYK2 while avoiding cross-reactivity with other JAK family members is essential for developing effective TYK2 inhibitors. However, designing inhibitors that target the catalytic ATP-binding site of TYK2 remains challenging due to the high structural similarity of this region across JAK family proteins.
Results
In this study, we developed a novel small molecule Zasocitinib inhibitor, QL-1200186, that specifically targets the pseudokinase regulatory domain (Janus homology 2, JH2) of TYK2. Binding sites for QL-1200186 were identified and screened through molecular docking. Its inhibitory effects on IFNα, IL-12, and IL-23 signaling were evaluated in cell lines, human peripheral blood cells, and whole blood. Pharmacokinetic (PK) and pharmacodynamic (PD) properties were assessed in mice.
QL-1200186 demonstrated high binding affinity for the TYK2 JH2 domain without significant selectivity for the homologous kinase domains of other JAK family members, as confirmed by biochemical binding assays, signaling pathway analyses (JAK1/2/3), and off-target effect evaluations. Importantly, QL-1200186 showed superior selectivity and comparable functional activity to two clinical-stage TYK2 inhibitors, BMS-986165 and NDI-034858, in vitro. In PK studies, QL-1200186 exhibited excellent systemic exposure, high bioavailability, and low clearance rates in mice. Furthermore, oral administration of QL-1200186 dose-dependently suppressed interferon-γ (IFNγ) production following interleukin-12 (IL-12) challenge and significantly improved psoriatic skin lesions in a mouse model.
Conclusion
QL-1200186 is a potent and highly selective TYK2 inhibitor with promising therapeutic potential. These results highlight its suitability as a clinical drug candidate for the treatment of psoriasis and other autoimmune diseases.