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Although biological TNF\u03b1 inhibitors revolutionized treatment, they have drawbacks including lacking blood\u2013brain barrier penetration, parenteral administration, and immunogenicity. Recent studies highlight the potential of small\u2010molecule approaches to target TNF\u03b1 by stabilizing an asymmetrical, receptor\u2010incompetent trimer conformation. Balinatunfib (also known as SAR441566) is an orally available small molecule designed to exploit this mechanism, thereby preventing TNF\u03b1 from effectively binding to its receptors. In preclinical models, balinatunfib reduces inflammation comparably to biologic therapies, yet avoids the complexities of large protein therapeutics. This allosteric strategy involves capturing a sampled but distorted state of TNF\u03b1, thereby blocking receptor clustering and downstream proinflammatory signaling. The oral route of administration confers practical advantages in terms of patient compliance and could facilitate drug access to sites traditionally less amenable to biologics, such as the central nervous system. By demonstrating that small molecules can achieve high\u2010affinity, conformation\u2010based inhibition of TNF\u03b1, balinatunfib, and related compounds may result in a new area of orally administered therapies that advance the management of TNF\u03b1\u2010mediated diseases.<\/jats:p>","DOI":"10.1002\/cmdc.202500258","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T00:20:21Z","timestamp":1750378821000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Balinatunfib: A Clinical Oral Small Molecule TNF\u03b1 Inhibitor"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9923-8873","authenticated-orcid":false,"given":"Alexander","family":"D\u00f6mling","sequence":"first","affiliation":[{"name":"Innovative Chemistry Group Institute for Molecular and Translational Medicine (IMTM) and Czech Advanced Technology and Research Institute (CATRIN) Univerzita Palack\u00e9ho v Olomouci  Olomouc 779 00 Czechia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tad A.","family":"Holak","sequence":"additional","affiliation":[{"name":"Department of Biomedical Chemistry Faculty of Chemistry University of Gda\u0144sk  Gda\u0144sk 80\u2010308 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,19]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.1037983"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00792-3"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-04-325225"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-023-01002-7"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-021-00584-4"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14112603"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1116304"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07882-8"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c01732"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20828-3"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c01280"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2021.06.018"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202500258","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T17:11:17Z","timestamp":1760289077000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.202500258"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,19]]},"references-count":12,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2025,7,18]]}},"alternative-id":["10.1002\/cmdc.202500258"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.202500258","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,19]]},"assertion":[{"value":"2025-04-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202500258"}}