Tyrosine kinase 2 (TYK2) JH1 catalytic domain (TYK2 JH1)

Tyrosine kinase 2 (TYK2) is a non-receptor tyrosine kinase belonging to the Janus kinase (JAK) family, essential for mediating signaling from type I interferons, IL-12, and IL-23 receptors (UniProt P29597). The JH1 catalytic domain is the C-terminal region of the protein responsible for its phosphotransferase activity, which phosphorylates STAT proteins to initiate gene transcription (PubMed: 27261270). Dysregulation of TYK2 signaling is a key driver in the pathogenesis of various autoimmune and inflammatory diseases, including psoriasis and systemic lupus erythematosus (NIH: PMC6541315). While the JH1 domain is the primary site for traditional ATP-competitive inhibitors, its high structural conservation across the JAK family makes achieving selectivity difficult (PubMed: 33237745). Consequently, many JH1-targeting drugs, such as brepocitinib and ropsacitinib, exhibit dual or pan-JAK activity, which can lead to off-target safety concerns like hematological abnormalities or increased infection risk (Frontiers in Immunology: 10.3389/fimmu.2023.1214318). In contrast, newer allosteric inhibitors target the JH2 pseudokinase domain to indirectly regulate JH1 activity with higher specificity (Nature: 10.1038/s41587-022-01331-z).

Other names

Non-receptor tyrosine-protein kinase TYK2 catalytic domainJanus kinase homology 1 domain of TYK2TYK2 kinase domainJTK1 catalytic domain

ATP-competitive inhibition of the catalytic domain