A Novel highly selective allosteric inhibitor of TYK2 can block inflammation/autoimmune pathways

Abstract

Abstract Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family, which plays an important part in signal transduction and regulation of the immune system. To minimize the safety concerns and improve the therapeutic effect against autoimmune diseases, we developed a small molecule inhibitor (QL-1200186) targeting the pseudokinase domain of TYK2 protein (JH2). The binding sites of QL-1200186 were predicted and screened by molecular docking. The inhibitory effects of the downstream signaling pathways and transcriptional activators of TYK2 were reflected in cell lines and human peripheral-blood cells. Pharmacokinetics and pharmacodynamics were verified in mice. QL-1200186 showed highly affinity to TYK2 JH2 and had no apparent selectivity for the TYK2 and JAK homologous kinase domains (JH1); these effects were manifested in assays based on biochemical binding, signaling pathway transduction (JAK1/2/3) and off-target effects. We revealed that currently available drugs, such as BMS-986165 and NDI-034858, were the most likely candidates for TYK2 inhibitors, and found that QL-1200186 was functionally comparable to and selectively superior to both agents in vitro. QL-1200186 showed excellent exposure, high bioavailability and afforded low clearance rates in mice. Oral administration of QL-1200186 dose-dependently inhibited interferon-γ production in interleukin-12-driven responses and ameliorated skin lesions significantly in a mouse model of psoriasis, respectively. These findings suggest that QL-1200186 is a highly selective and potent inhibitor of TYK2. QL-1200186 could be developed as a drug for the treatment of psoriasis or other autoimmune diseases.