{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T14:29:49Z","timestamp":1774016989137,"version":"3.50.1"},"reference-count":27,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:00:00Z","timestamp":1772755200000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004312","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Receptor\u2010interacting serine\/threonine\u2010protein kinase 1 (RIPK1) inhibitors are being investigated for chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis. Ocadusertib is a potent and selective allosteric inhibitor of RIPK1 and is currently being studied in clinical trials. Here, we present data on the development of ocadusertib, including preclinical studies and pharmacokinetic, safety, and target engagement results from phase 1 trials. Preclinically, ocadusertib inhibited RIPK1 enzymatic activity with high potency (half\u2010maximal inhibitory concentration [IC\n                    <jats:sub>50<\/jats:sub>\n                    ]\u2009=\u200912\u201338\u2009nM) and inhibited necroptotic responses in multiple cell\u2010based assays. Ocadusertib was highly selective for RIPK1, showing no significant inhibition of more than 100 other kinases representative of the full kinome. In mouse studies, ocadusertib treatment prevented RIPK1\u2010dependent hypothermia in response to tumor necrosis factor (TNF) challenge and significantly reduced disease severity in a model of chronic proliferative dermatitis. In a first\u2010in\u2010human study of ocadusertib in healthy participants, single oral doses exhibited linear pharmacokinetics and dose\u2010proportional exposure, with a time to maximum concentration of 1\u20134\u2009h and a half\u2010life of 13\u201315\u2009h. Steady state was attained at 4\u20136\u2009days after multiple once\u2010daily dose administrations. Ocadusertib was well tolerated, with no deaths, serious adverse events, or significant treatment\u2010emergent adverse events reported. In a phase 1, double\u2010blind, randomized, multiple\u2010dose study in healthy participants, greater than 90% RIPK1 target engagement was achieved at Day 14 with ocadusertib treatment. Taken together, these findings support further assessment of ocadusertib for the treatment of chronic inflammatory diseases.\n                  <\/jats:p>","DOI":"10.1111\/cts.70519","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T10:22:12Z","timestamp":1772965332000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Early Development of Ocadusertib, a Selective Receptor\u2010Interacting Serine\/Threonine\u2010Protein Kinase 1 Inhibitor"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0548-1881","authenticated-orcid":false,"given":"Simon J.","family":"Shaw","sequence":"first","affiliation":[{"name":"Rigel Pharmaceuticals, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8163-1827","authenticated-orcid":false,"given":"Vanessa C.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Rigel Pharmaceuticals, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8599-2157","authenticated-orcid":false,"given":"Jonathan T.","family":"Sims","sequence":"additional","affiliation":[{"name":"Immunology Discovery, Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Ho","sequence":"additional","affiliation":[{"name":"Immunology Discovery, Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7557-5535","authenticated-orcid":false,"given":"Chrystelle","family":"Lamagna","sequence":"additional","affiliation":[{"name":"Rigel Pharmaceuticals, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucy","family":"Yan","sequence":"additional","affiliation":[{"name":"Rigel Pharmaceuticals, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas C.","family":"Reising","sequence":"additional","affiliation":[{"name":"Neuroscience Discovery, Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2064-2424","authenticated-orcid":false,"given":"Andrew","family":"Chow","sequence":"additional","affiliation":[{"name":"Rigel Pharmaceuticals, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0318-4779","authenticated-orcid":false,"given":"Eric P.","family":"Hanson","sequence":"additional","affiliation":[{"name":"Immunology Discovery, Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6466-348X","authenticated-orcid":false,"given":"Andrew C.","family":"Vendel","sequence":"additional","affiliation":[{"name":"Immunology Discovery, Eli Lilly and Company  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel J.","family":"Dairaghi","sequence":"additional","affiliation":[{"name":"Immunology Discovery, Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3175-2868","authenticated-orcid":false,"given":"Esteban S.","family":"Masuda","sequence":"additional","affiliation":[{"name":"Rigel Pharmaceuticals, Inc.  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ClinicalTrials.gov Identifier: NCT04781816 \u201dupdated June 24 2024 accessed June 16 2025 https:\/\/clinicaltrials.gov\/study\/NCT04781816."},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075\u2010021\u201002468\u20100"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjgast\u20102021\u2010000680"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70519","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.70519","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70519","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T12:37:52Z","timestamp":1774010272000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.70519"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3]]},"references-count":27,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1111\/cts.70519"],"URL":"https:\/\/doi.org\/10.1111\/cts.70519","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3]]},"assertion":[{"value":"2025-08-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-06","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70519"}}