Selective tyrosine kinase 2 inhibitors in inflammatory bowel disease

Tyrosine kinase 2 (TYK2), which is part of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, is implicated in the pathophysiology of various immune-mediated inflammatory diseases, including inflammatory bowel disease (IBD). Different nonspecific JAK inhibitors suppress various cytokine signals but display serious side effects, such as bone marrow suppression, risk of serious infections (particularly shingles), and thromboembolism. TYK2 contains a JAK homology 2 (JH2) pseudokinase domain that acts as a regulator of its JH1 kinase domain responsible for receptor activation. Recently, a TYK2-specific inhibitor, deucravacitinib, that binds allosterically to the JH2 domain and prevents receptor-mediated activation, has been developed. Deucravacitinib and other TYK2 inhibitors are currently being tested in Phase II studies for both ulcerative colitis and Crohn disease. Although data on adverse events in IBD are still scarce, no serious infections or thrombotic events have been reported. Recent significant advances have been made in the treatment of chronic inflammatory diseases with initiation of the era of biologics. However, an unmet medical need still exists for novel targeted therapies. Compared with biologics, Janus kinase inhibitors (JAKis) are a new drug class of orally administered small molecules that have been shown to efficiently modulate complex cytokine-driven inflammation in preclinical models and human studies. Unfortunately, serious adverse effects have been reported with the first introduced pan-JAKi, tofacitinib. Here, we review tyrosine kinase 2 (TYK2) signaling in the pathophysiology of inflammatory bowel disease (IBD), examine mechanisms of action of selective TYK2 inhibitors (TYK2is), and discuss the potential for these inhibitors in efforts to balance benefits and harms. Recent significant advances have been made in the treatment of chronic inflammatory diseases with initiation of the era of biologics. However, an unmet medical need still exists for novel targeted therapies. Compared with biologics, Janus kinase inhibitors (JAKis) are a new drug class of orally administered small molecules that have been shown to efficiently modulate complex cytokine-driven inflammation in preclinical models and human studies. Unfortunately, serious adverse effects have been reported with the first introduced pan-JAKi, tofacitinib. Here, we review tyrosine kinase 2 (TYK2) signaling in the pathophysiology of inflammatory bowel disease (IBD), examine mechanisms of action of selective TYK2 inhibitors (TYK2is), and discuss the potential for these inhibitors in efforts to balance benefits and harms. modulation of protein activity by ligand binding to a site distinct from the active site of the protein. also known as 'NUAK1,' ARK5 belongs to the AMP-activated protein kinase catalytic subunit family and functions as a key regulator of cellular energy homeostasis. a subtype of IBD that can cause inflammation in any part of the gastrointestinal tract, but most commonly involves both the small and large intestines. observational studies focusing on associations between different genetic variants, typically between SNPs. a group of chronic intestinal disorders that cause prolonged inflammation of the digestive tract. small molecule Janus kinase inhibitors. family of non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK/STAT pathway. mathematical evaluation of representations of the physical contacts between proteins in the cell. catalytically deficient pseudoenzyme variants of protein kinases that have evolved alongside their enzymatically active counterparts. a family of transcription factors consisting of seven structurally and functionally related proteins: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6. Hence, they act as signal transducers in the cytoplasm and transcription activators in the nucleus when cells encounter cytokines and growth factors. germline substitution of a specific single nucleotide. non-receptor tyrosine protein kinase that is part of the JAK family; the other members are JAK1, JAK2, and JAK3. the most prevalent subtype of inflammatory bowel disease causing irritation, inflammation, and ulcers in the lining of the colon (large intestine) only.