{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:12:03Z","timestamp":1791389523164,"version":"4.3.3"},"reference-count":16,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T00:00:00Z","timestamp":1691020800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004012","name":"Jane and Aatos Erkko Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004012","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006306","name":"Sigrid Jus\u00e9lius Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006306","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006706","name":"Tampere Tuberculosis Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006706","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The selectivity of JAK inhibitors (Jakinibs) forms the basis for understanding their clinical characteristics; however, evaluation of selectivity is hampered by the lack of comprehensive head\u2010to\u2010head studies. Our objective was to profile in parallel Jakinibs indicated or evaluated for rheumatic diseases for their JAK and cytokine selectivity in vitro.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed 10 Jakinibs for JAK isoform selectivity by assaying their inhibition of JAK kinase activity, binding to kinase and pseudokinase domains, and inhibition of cytokine signaling using blood samples from healthy volunteers and using isolated peripheral blood mononuclear cells (PBMCs) from patients with rheumatoid arthritis and from healthy donors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Pan\u2010Jakinibs effectively suppressed kinase activity of 2 to 3 JAK family members, whereas isoform\u2010targeted Jakinibs possessed varying degrees of selectivity for 1 or 2 JAK family members. In human leukocytes, Jakinibs predominantly inhibited the JAK1\u2010dependent cytokines interleukin\u20102 (IL\u20102), IL\u20106, and interferons (IFNs). In PBMCs from patients with rheumatoid arthritis compared with healthy controls, inhibition of these cytokines was more pronounced, and some cell\u2010type and STAT isoform differences were observed. Novel Jakinibs demonstrated high selectivity: the covalent Jakinib ritlecitinib showed 900\u2010 to 2,500\u2010fold selectivity for JAK3 over other JAKs and specific suppression of IL\u20102\u2010signaling, whereas the allosteric TYK2 inhibitor deucravacitinib inhibited IFN\u03b1 signaling with high specificity. Interestingly, deucravacitinib targeted the regulatory pseudokinase domain and did not affect JAK in vitro kinase activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Inhibition of JAK kinase activity did not directly translate into cellular inhibition of JAK\/STAT signaling. Despite differences in JAK selectivity, the cytokine inhibition profiles of currently approved Jakinibs were highly similar, with preference for JAK1\u2010mediated cytokines. Novel types of Jakinibs showed narrow cytokine inhibition profile specific for JAK3\u2010 or TYK2\u2010mediated signaling.<\/jats:p>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art42547-toc-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.42547","type":"journal-article","created":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T13:54:00Z","timestamp":1683122040000},"page":"2054-2061","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Differences in\n                    <scp>JAK<\/scp>\n                    Isoform Selectivity Among Different Types of\n                    <scp>JAK<\/scp>\n                    Inhibitors Evaluated for Rheumatic Diseases Through In Vitro Profiling"],"prefix":"10.1002","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7332-4880","authenticated-orcid":false,"given":"Anniina","family":"Virtanen","sequence":"first","affiliation":[{"name":"Institute of Biotechnology, HiLIFE Helsinki Institute of Life Science, University of Helsinki, Helsinki, and Faculty of Medicine and Health Technology Tampere University  Tampere Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maaria","family":"Palmroth","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology Tampere University  Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanna","family":"Liukkonen","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology Tampere University  Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antti","family":"Kurttila","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology Tampere University  Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teemu","family":"Haikarainen","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology, Tampere University, and Fimlab Laboratories  Tampere Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia","family":"Isom\u00e4ki","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology, Tampere University, and Centre for Rheumatic Diseases, Tampere University Hospital  Tampere Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olli","family":"Silvennoinen","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, HiLIFE Helsinki Institute of Life Science, University of Helsinki, Helsinki, and Faculty of Medicine and Health Technology, Tampere University, Tempere, and Fimlab Laboratories  Tampere Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,8,3]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2018.03.041"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.02.006"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2015.171"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40259-019-00333-w"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b00444"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.6b00677"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/cb5002125"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules26164898"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-019-1964-1"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2020-219012"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.537"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41316"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2021-221664"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s41927-018-0031-x"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/17425255.2021.1862084"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40569"}],"container-title":["Arthritis &amp; 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