{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T20:23:30Z","timestamp":1788985410766,"version":"build-2803163510"},"reference-count":56,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2021,6,5]],"date-time":"2021-06-05T00:00:00Z","timestamp":1622851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008021","name":"Bristol Myers Squibb","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008021","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Conventional systemic and biologic agents are the mainstay of inflammatory bowel disease (IBD) management; however, many of these agents are associated with loss of clinical response, highlighting the need for effective, novel targeted therapies. Janus kinase (JAK) 1-3 and tyrosine kinase 2 (TYK2) mediate signal transduction events downstream of multiple cytokine receptors that regulate targeted gene transcription, including the interleukin-12, interleukin-23, and type I interferon receptors for TYK2. This review summarizes the role of TYK2 signaling in IBD pathogenesis, the differential selectivity of TYK2 inhibitors, and the potential clinical implications of TYK2 inhibition in IBD. A PubMed literature review was conducted to identify studies of JAK1-3 and TYK2 inhibitors in IBD and other immune-mediated inflammatory diseases. Key efficacy and safety information was extracted and summarized. Pan-JAK inhibitors provide inconsistent efficacy in patients with IBD and are associated with toxicities resulting from a lack of selectivity at therapeutic dosages. Selective inhibition of TYK2 signaling via an allosteric mechanism, with an agent that binds to the regulatory (pseudokinase) domain, may reduce potential toxicities typically associated with JAK1-3 inhibitors. Deucravacitinib, a novel, oral, selective TYK2 inhibitor, and brepocitinib and PF-06826647, TYK2 inhibitors that bind to the active site in the catalytic domain, are in development for IBD and other immune-mediated inflammatory diseases. Allosteric TYK2 inhibition is more selective than JAK1-3 inhibition and has the potential to limit toxicities typically associated with JAK1-3 inhibitors. Future studies will be important in establishing the role of selective, allosteric TYK2 inhibition in the management of IBD.<\/jats:p>","DOI":"10.1093\/ibd\/izab135","type":"journal-article","created":{"date-parts":[[2021,6,5]],"date-time":"2021-06-05T06:08:45Z","timestamp":1622873325000},"page":"2023-2030","source":"Crossref","is-referenced-by-count":68,"title":["Selective Tyrosine Kinase 2 Inhibition for Treatment of Inflammatory Bowel Disease: New Hope on the Rise"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7341-1351","authenticated-orcid":false,"given":"Silvio","family":"Danese","sequence":"first","affiliation":[{"name":"Humanitas University and IBD Center, Istituto Clinico Humanitas , Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Peyrin-Biroulet","sequence":"additional","affiliation":[{"name":"Department of Hepato-Gastroenterology, Nancy University Hospital, Lorraine University , Vand\u0153uvre-l\u00e8s-Nancy , France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,6,5]]},"reference":[{"key":"2023112501264163400_CIT0001","first-page":"173","article-title":"Psychosocial factors contributing to inflammatory bowel disease activity and health-related quality of life","volume":"8","author":"Faust","year":"2012","journal-title":"Gastroenterol Hepatol (N Y)."},{"key":"2023112501264163400_CIT0002","volume-title":"The facts about inflammatory bowel diseases"},{"key":"2023112501264163400_CIT0003","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/nrgastro.2015.186","article-title":"Immunopathogenesis of IBD: current state of the art","volume":"13","author":"de Souza","year":"2016","journal-title":"Nat Rev Gastroenterol Hepatol."},{"key":"2023112501264163400_CIT0004","doi-asserted-by":"crossref","first-page":"25","DOI":"10.4110\/in.2017.17.1.25","article-title":"Pathogenesis of inflammatory bowel disease and recent advances in biologic therapies","volume":"17","author":"Kim","year":"2017","journal-title":"Immune Netw."},{"key":"2023112501264163400_CIT0005","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1080\/00365521.2018.1447597","article-title":"Immunopathogenesis of inflammatory bowel disease and mechanisms of biological therapies","volume":"53","author":"Ahluwalia","year":"2018","journal-title":"Scand J Gastroenterol."},{"key":"2023112501264163400_CIT0006","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.imlet.2015.10.004","article-title":"Innate lymphoid cells in inflammatory bowel diseases","volume":"172","author":"Peters","year":"2016","journal-title":"Immunol Lett."},{"key":"2023112501264163400_CIT0007","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nri3661","article-title":"Cytokines in inflammatory bowel disease","volume":"14","author":"Neurath","year":"2014","journal-title":"Nat Rev Immunol."},{"key":"2023112501264163400_CIT0008","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.bpg.2018.05.016","article-title":"Can IL-23 be a good target for ulcerative colitis?","volume":"32\u201333","author":"Allocca","year":"2018","journal-title":"Best Pract Res Clin Gastroenterol."},{"key":"2023112501264163400_CIT0009","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cytogfr.2018.12.002","article-title":"IL-23 in inflammatory bowel diseases and colon cancer","volume":"45","author":"Neurath","year":"2019","journal-title":"Cytokine Growth Factor Rev."},{"key":"2023112501264163400_CIT0010","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/ajg.2018.27","article-title":"ACG clinical guideline: management of Crohn\u2019s disease in adults","volume":"113","author":"Lichtenstein","year":"2018","journal-title":"Am J Gastroenterol."},{"key":"2023112501264163400_CIT0011","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1111\/j.1365-2036.2011.04599.x","article-title":"Review article: remission rates achievable by current therapies for inflammatory bowel disease","volume":"33","author":"Peyrin-Biroulet","year":"2011","journal-title":"Aliment Pharmacol Ther."},{"key":"2023112501264163400_CIT0012","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1111\/apt.14669","article-title":"Review article: novel oral-targeted therapies in inflammatory bowel disease","volume":"47","author":"White","year":"2018","journal-title":"Aliment Pharmacol Ther."},{"key":"2023112501264163400_CIT0013","doi-asserted-by":"crossref","first-page":"G155","DOI":"10.1152\/ajpgi.00311.2015","article-title":"JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines","volume":"310","author":"Danese","year":"2016","journal-title":"Am J Physiol Gastrointest Liver Physiol."},{"key":"2023112501264163400_CIT0014","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1136\/gutjnl-2016-312912","article-title":"Next generation of small molecules in inflammatory bowel disease","volume":"66","author":"Olivera","year":"2017","journal-title":"Gut."},{"key":"2023112501264163400_CIT0015","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1080\/13543784.2018.1492547","article-title":"Janus kinase inhibitors for the treatment of inflammatory bowel diseases: developments from phase I and phase II clinical trials","volume":"27","author":"D\u2019Amico","year":"2018","journal-title":"Expert Opin Investig Drugs."},{"key":"2023112501264163400_CIT0016","doi-asserted-by":"crossref","first-page":"S746","DOI":"10.1093\/ecco-jcc\/jjz186","article-title":"JAK efficacy in Crohn\u2019s disease","volume":"14","author":"Rogler","year":"2020","journal-title":"J Crohns Colitis."},{"key":"2023112501264163400_CIT0017","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1111\/apt.14486","article-title":"Editorial: tofacitinib and biologics for moderate-to-severe ulcerative colitis\u2014what is best in class? Authors\u2019 reply","volume":"47","author":"Bonovas","year":"2018","journal-title":"Aliment Pharmacol Ther."},{"key":"2023112501264163400_CIT0018","doi-asserted-by":"crossref","first-page":"i34","DOI":"10.1093\/rheumatology\/key287","article-title":"Growing evidence of the safety of JAK inhibitors in patients with rheumatoid arthritis","volume":"58","author":"Harigai","year":"2019","journal-title":"Rheumatology (Oxford)."},{"key":"2023112501264163400_CIT0019","doi-asserted-by":"crossref","first-page":"212","DOI":"10.3389\/fphar.2019.00212","article-title":"Targeting cytokine signaling and lymphocyte traffic via small molecules in inflammatory bowel disease: JAK inhibitors and S1PR agonists","volume":"10","author":"P\u00e9rez-Jeldres","year":"2019","journal-title":"Front Pharmacol."},{"key":"2023112501264163400_CIT0020","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1136\/gutjnl-2019-318448","article-title":"JAK selectivity for inflammatory bowel disease treatment: does it clinically matter?","volume":"68","author":"Danese","year":"2019","journal-title":"Gut."},{"key":"2023112501264163400_CIT0021","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s40265-020-01261-8","article-title":"JAK inhibitors for treatment of psoriasis: focus on selective TYK2 inhibitors","volume":"80","author":"Nogueira","year":"2020","journal-title":"Drugs."},{"key":"2023112501264163400_CIT0022","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/s41575-020-0273-0","article-title":"JAK-STAT pathway targeting for the treatment of inflammatory bowel disease","volume":"17","author":"Salas","year":"2020","journal-title":"Nat Rev Gastroenterol Hepatol."},{"key":"2023112501264163400_CIT0023","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1136\/annrheumdis-2017-211555","article-title":"Novel therapies for immune-mediated inflammatory diseases: what can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn\u2019s disease and ulcerative colitis?","volume":"77","author":"Baker","year":"2018","journal-title":"Ann Rheum Dis."},{"key":"2023112501264163400_CIT0024","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1126\/scitranslmed.aaw1736","article-title":"Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain","volume":"11","author":"Burke","year":"2019","journal-title":"Sci Transl Med."},{"key":"2023112501264163400_CIT0025","doi-asserted-by":"crossref","first-page":"28066","DOI":"10.1074\/jbc.M805545200","article-title":"Leptin stimulates both JAK2-dependent and JAK2-independent signaling pathways","volume":"283","author":"Jiang","year":"2008","journal-title":"J Biol Chem."},{"key":"2023112501264163400_CIT0026","doi-asserted-by":"crossref","first-page":"14020","DOI":"10.1074\/jbc.M112399200","article-title":"Role of tyrosine kinase Jak2 in prolactin-induced differentiation and growth of mammary epithelial cells","volume":"277","author":"Xie","year":"2002","journal-title":"J Biol Chem."},{"key":"2023112501264163400_CIT0027","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s13555-019-00347-w","article-title":"Systemic treatment of psoriasis with JAK inhibitors: a review","volume":"10","author":"Kvist-Hansen","year":"2020","journal-title":"Dermatol Ther (Heidelb)."},{"key":"2023112501264163400_CIT0028","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1080\/14728214.2020.1745773","article-title":"Emerging systemic drugs in the treatment of plaque psoriasis","volume":"25","author":"Balogh","year":"2020","journal-title":"Expert Opin Emerg Drugs."},{"key":"2023112501264163400_CIT0029","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/j.1600-065X.2008.00754.x","article-title":"Janus kinases in immune cell signaling","volume":"228","author":"Ghoreschi","year":"2009","journal-title":"Immunol Rev."},{"key":"2023112501264163400_CIT0030","doi-asserted-by":"crossref","first-page":"11061","DOI":"10.1074\/jbc.M114.619502","article-title":"Tyrosine kinase 2-mediated signal transduction in T lymphocytes is blocked by pharmacological stabilization of its pseudokinase domain","volume":"290","author":"Tokarski","year":"2015","journal-title":"J Biol Chem."},{"key":"2023112501264163400_CIT0031","first-page":"S2","article-title":"Pathogenesis and treatment of psoriasis: exploiting pathophysiological pathways for precision medicine","volume":"33","author":"Alwan","year":"2015","journal-title":"Clin Exp Rheumatol."},{"key":"2023112501264163400_CIT0032","doi-asserted-by":"crossref","first-page":"3116","DOI":"10.4049\/jimmunol.1101313","article-title":"Type I IFN drives a distinctive dendritic cell maturation phenotype that allows continued class II MHC synthesis and antigen processing","volume":"188","author":"Simmons","year":"2012","journal-title":"J Immunol."},{"key":"2023112501264163400_CIT0033","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1007\/s00109-016-1421-4","article-title":"Cause and consequences of the activated type I interferon system in SLE","volume":"94","author":"Eloranta","year":"2016","journal-title":"J Mol Med (Berl)."},{"key":"2023112501264163400_CIT0034","doi-asserted-by":"crossref","first-page":"20059","DOI":"10.1074\/jbc.R700016200","article-title":"JAK-STAT signaling: from interferons to cytokines","volume":"282","author":"Schindler","year":"2007","journal-title":"J Biol Chem."},{"key":"2023112501264163400_CIT0035","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1016\/S0002-9440(10)63403-7","article-title":"Roles and regulation of STAT family transcription factors in human breast cancer","volume":"165","author":"Clevenger","year":"2004","journal-title":"Am J Pathol."},{"key":"2023112501264163400_CIT0036","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.4049\/jimmunol.1202859","article-title":"A restricted role for TYK2 catalytic activity in human cytokine responses revealed by novel TYK2-selective inhibitors","volume":"191","author":"Sohn","year":"2013","journal-title":"J Immunol."},{"key":"2023112501264163400_CIT0037","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S1074-7613(00)00054-6","article-title":"Partial impairment of cytokine responses in Tyk2-deficient mice","volume":"13","author":"Karaghiosoff","year":"2000","journal-title":"Immunity."},{"key":"2023112501264163400_CIT0038","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.immuni.2006.09.009","article-title":"Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity","volume":"25","author":"Minegishi","year":"2006","journal-title":"Immunity."},{"key":"2023112501264163400_CIT0039","doi-asserted-by":"crossref","first-page":"29","DOI":"10.3389\/fimmu.2017.00029","article-title":"Canonical and non-canonical aspects of JAK-STAT signaling: lessons from interferons for cytokine responses","volume":"8","author":"Majoros","year":"2017","journal-title":"Front Immunol."},{"key":"2023112501264163400_CIT0040","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1093\/intimm\/dxt062","article-title":"Tyk2 is a therapeutic target for psoriasis-like skin inflammation","volume":"26","author":"Ishizaki","year":"2014","journal-title":"Int Immunol."},{"key":"2023112501264163400_CIT0041","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.immuni.2019.03.020","article-title":"IL-10 family cytokines IL-10 and IL-22: from basic science to clinical translation","volume":"50","author":"Ouyang","year":"2019","journal-title":"Immunity."},{"key":"2023112501264163400_CIT0042","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cyto.2014.10.031","article-title":"Interleukin-10 paradox: a potent immunoregulatory cytokine that has been difficult to harness for immunotherapy","volume":"74","author":"Saxena","year":"2015","journal-title":"Cytokine."},{"key":"2023112501264163400_CIT0043","doi-asserted-by":"crossref","first-page":"363ra149","DOI":"10.1126\/scitranslmed.aag1974","article-title":"Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity","volume":"8","author":"Dendrou","year":"2016","journal-title":"Sci Transl Med."},{"key":"2023112501264163400_CIT0044","doi-asserted-by":"crossref","first-page":"8597","DOI":"10.1021\/acs.jmedchem.8b00917","article-title":"Dual inhibition of TYK2 and JAK1 for the treatment of autoimmune diseases: discovery of ((S)-2,2-difluorocyclopropyl)((1 R,5 S)-3-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841)","volume":"61","author":"Fensome","year":"2018","journal-title":"J Med Chem."},{"key":"2023112501264163400_CIT0045","doi-asserted-by":"crossref","first-page":"8973","DOI":"10.1021\/acs.jmedchem.9b00444","article-title":"Highly selective inhibition of tyrosine kinase 2 (TYK2) for the treatment of autoimmune diseases: discovery of the allosteric inhibitor BMS-986165","volume":"62","author":"Wrobleski","year":"2019","journal-title":"J Med Chem."},{"key":"2023112501264163400_CIT0046","first-page":"37","article-title":"A Phase 2A, randomised, double-blind, placebo-controlled study to evaluate efficacy and safety of PF-06700841 in patients with moderate-to-severe plaque psoriasis [abstract 86]","volume-title":"Exp Dermatol.","author":"Forman","year":"2018"},{"key":"2023112501264163400_CIT0047","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1016\/j.jid.2019.11.027","article-title":"Molecular and cellular responses to the TYK2\/JAK1 inhibitor PF-06700841 reveal reduction of skin inflammation in plaque psoriasis","volume":"140","author":"Page","year":"2020","journal-title":"J Invest Dermatol."},{"key":"2023112501264163400_CIT0048","doi-asserted-by":"crossref","first-page":"13561","DOI":"10.1021\/acs.jmedchem.0c00948","article-title":"Discovery of tyrosine kinase 2 (TYK2) inhibitor (PF-06826647) for the treatment of autoimmune diseases","volume":"63","author":"Gerstenberger","year":"2020","journal-title":"J Med Chem."},{"key":"2023112501264163400_CIT0049","doi-asserted-by":"crossref","first-page":"e204","DOI":"10.1016\/S2665-9913(20)30397-0","article-title":"Safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamics of the oral TYK2 inhibitor PF-06826647 in participants with plaque psoriasis: a phase 1, randomised, double-blind, placebo-controlled, parallel-group study","volume":"3","author":"Tehlirian","year":"2021","journal-title":"Lancet Rheumatol."},{"key":"2023112501264163400_CIT0050","doi-asserted-by":"crossref","first-page":"8953","DOI":"10.1021\/acs.jmedchem.9b00443","article-title":"Identification of N-methyl nicotinamide and N-methyl pyridazine-3-carboxamide pseudokinase domain ligands as highly selective allosteric inhibitors of tyrosine kinase 2 (TYK2)","volume":"62","author":"Moslin","year":"2019","journal-title":"J Med Chem."},{"key":"2023112501264163400_CIT0051","doi-asserted-by":"crossref","first-page":"8951","DOI":"10.1021\/acs.jmedchem.9b01612","article-title":"Tyrosine kinase 2 (TYK2) allosteric inhibitors to treat autoimmune diseases","volume":"62","author":"Chang","year":"2019","journal-title":"J Med Chem."},{"key":"2023112501264163400_CIT0052","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1056\/NEJMoa1806382","article-title":"Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis","volume":"379","author":"Papp","year":"2018","journal-title":"N Engl J Med."},{"key":"2023112501264163400_CIT0053","doi-asserted-by":"crossref","article-title":"BMS-986165, an oral, selective tyrosine kinase 2 (TYK2) inhibitor: evaluation of changes in laboratory parameters in response to treatment in a Phase 2 trial in psoriasis patients","author":"Gordon","DOI":"10.25251\/skin.4.supp.28"},{"key":"2023112501264163400_CIT0054","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/nrrheum.2017.23","article-title":"The emerging safety profile of JAK inhibitors in rheumatic disease","volume":"13","author":"Winthrop","year":"2017","journal-title":"Nat Rev Rheumatol."},{"key":"2023112501264163400_CIT0055","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1002\/jcph.1046","article-title":"The safety, tolerability, pharmacokinetics, and pharmacodynamics of a TYK2\/JAK1 inhibitor (PF-06700841) in healthy subjects and patients with plaque psoriasis","volume":"58","author":"Banfield","year":"2018","journal-title":"J Clin Pharmacol."},{"key":"2023112501264163400_CIT0056","article-title":"A selective inhibitor of TYK2, BMS-986165, improves molecular, cellular and clinical biomarkers associated with efficacy in moderate-to-severe psoriasis","author":"Krueger"}],"container-title":["Inflammatory Bowel Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ibdjournal\/article-pdf\/27\/12\/2023\/53788650\/izab135.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ibdjournal\/article-pdf\/27\/12\/2023\/53788650\/izab135.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T20:28:14Z","timestamp":1700857694000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ibdjournal\/article\/27\/12\/2023\/6293782"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,5]]},"references-count":56,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,6,5]]},"published-print":{"date-parts":[[2021,11,15]]}},"URL":"https:\/\/doi.org\/10.1093\/ibd\/izab135","relation":{},"ISSN":["1078-0998","1536-4844"],"issn-type":[{"value":"1078-0998","type":"print"},{"value":"1536-4844","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,12,1]]},"published":{"date-parts":[[2021,6,5]]}}}