An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis
Tumor necrosis factor (TNF) is a pleiotropic cytokine belonging to a family of trimeric proteins with both proinflammatory and immunoregulatory functions. TNF is a key mediator in autoimmune diseases and during the last couple of decades several biologic drugs have delivered new therapeutic options...
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1037983/full |
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| author | Alexander Vugler James O’Connell Mai Anh Nguyen Dietmar Weitz Thomas Leeuw Elizabeth Hickford Alexander Verbitsky Xiaoyou Ying Markus Rehberg Bruce Carrington Mark Merriman Andrew Moss Jean-Marie Nicholas Phil Stanley Sara Wright Tim Bourne Yann Foricher Zhaoning Zhu Daniel Brookings Helen Horsley Jag Heer Laurent Schio Matthias Herrmann Srinivas Rao Markus Kohlmann Peter Florian |
| author_facet | Alexander Vugler James O’Connell Mai Anh Nguyen Dietmar Weitz Thomas Leeuw Elizabeth Hickford Alexander Verbitsky Xiaoyou Ying Markus Rehberg Bruce Carrington Mark Merriman Andrew Moss Jean-Marie Nicholas Phil Stanley Sara Wright Tim Bourne Yann Foricher Zhaoning Zhu Daniel Brookings Helen Horsley Jag Heer Laurent Schio Matthias Herrmann Srinivas Rao Markus Kohlmann Peter Florian |
| author_sort | Alexander Vugler |
| collection | DOAJ |
| description | Tumor necrosis factor (TNF) is a pleiotropic cytokine belonging to a family of trimeric proteins with both proinflammatory and immunoregulatory functions. TNF is a key mediator in autoimmune diseases and during the last couple of decades several biologic drugs have delivered new therapeutic options for patients suffering from chronic autoimmune diseases such as rheumatoid arthritis and chronic inflammatory bowel disease. Attempts to design small molecule therapies directed to this cytokine have not led to approved products yet. Here we report the discovery and development of a potent small molecule inhibitor of TNF that was recently moved into phase 1 clinical trials. The molecule, SAR441566, stabilizes an asymmetrical form of the soluble TNF trimer, compromises downstream signaling and inhibits the functions of TNF in vitro and in vivo. With SAR441566 being studied in healthy volunteers we hope to deliver a more convenient orally bioavailable and effective treatment option for patients suffering with chronic autoimmune diseases compared to established biologic drugs targeting TNF. |
| format | Article |
| id | doaj-art-1ee03f08f53b498dba01c240aad2ca37 |
| institution | OA Journals |
| issn | 1663-9812 |
| language | English |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-1ee03f08f53b498dba01c240aad2ca372025-08-20T02:16:49ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-11-011310.3389/fphar.2022.10379831037983An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritisAlexander Vugler0James O’Connell1Mai Anh Nguyen2Dietmar Weitz3Thomas Leeuw4Elizabeth Hickford5Alexander Verbitsky6Xiaoyou Ying7Markus Rehberg8Bruce Carrington9Mark Merriman10Andrew Moss11Jean-Marie Nicholas12Phil Stanley13Sara Wright14Tim Bourne15Yann Foricher16Zhaoning Zhu17Daniel Brookings18Helen Horsley19Jag Heer20Laurent Schio21Matthias Herrmann22Srinivas Rao23Markus Kohlmann24Peter Florian25Immunology Therapeutic Area, PV Early Solutions, UCB Pharma, Slough, United KingdomDiscovery Sciences, PV Early Solutions, UCB Pharma, Slough, United KingdomSanofi R&D, TMED Pharmacokinetics Dynamics and Metabolism, Frankfurt am Main, GermanySanofi R&D, Drug Metabolism and Pharmacokinetics, Frankfurt am Main, GermanySanofi R&D, Type 1/17 Immunology, Immunology & Inflammation Research TA, Frankfurt, GermanyDevelopment Science, PV Early Solutions, UCB Pharma, Slough, United KingdomSanofi R&D, Translation In vivo Models, Cambridge, MA, United StatesSanofi R&D, Translation In vivo Models, Cambridge, MA, United StatesSanofi R&D, Translational Disease Modelling, Frankfurt am Main, GermanyDiscovery Sciences, PV Early Solutions, UCB Pharma, Slough, United KingdomImmunology Therapeutic Area, PV Early Solutions, UCB Pharma, Slough, United KingdomTranslational Medicine Immunology, PV Early Solutions, UCB Pharma, Slough, United Kingdom0Development Science, Drug Metabolism and Pharmacokinetics, UCB Pharma, Braine-I’Alleud, BelgiumImmunology Therapeutic Area, PV Early Solutions, UCB Pharma, Slough, United Kingdom1Early PV Missions, PV Early Solutions, UCB Pharma, Slough, United Kingdom2Milvuswood Consultancy, Penn, United Kingdom3Sanofi R&D, Integrated Drug Discovery, Vitry-sur-Seine, France4Global Chemistry, Discovery Sciences, PV Early Solutions, UCB Pharma, Slough, United Kingdom4Global Chemistry, Discovery Sciences, PV Early Solutions, UCB Pharma, Slough, United Kingdom4Global Chemistry, Discovery Sciences, PV Early Solutions, UCB Pharma, Slough, United Kingdom4Global Chemistry, Discovery Sciences, PV Early Solutions, UCB Pharma, Slough, United Kingdom3Sanofi R&D, Integrated Drug Discovery, Vitry-sur-Seine, FranceSanofi R&D, Type 1/17 Immunology, Immunology & Inflammation Research TA, Frankfurt, GermanySanofi R&D, Translation In vivo Models, Cambridge, MA, United States5Sanofi R&D, Early Clinical Development, Therapeutic Area Immunology and Inflammation, Frankfurt am Main, GermanySanofi R&D, Type 1/17 Immunology, Immunology & Inflammation Research TA, Frankfurt, GermanyTumor necrosis factor (TNF) is a pleiotropic cytokine belonging to a family of trimeric proteins with both proinflammatory and immunoregulatory functions. TNF is a key mediator in autoimmune diseases and during the last couple of decades several biologic drugs have delivered new therapeutic options for patients suffering from chronic autoimmune diseases such as rheumatoid arthritis and chronic inflammatory bowel disease. Attempts to design small molecule therapies directed to this cytokine have not led to approved products yet. Here we report the discovery and development of a potent small molecule inhibitor of TNF that was recently moved into phase 1 clinical trials. The molecule, SAR441566, stabilizes an asymmetrical form of the soluble TNF trimer, compromises downstream signaling and inhibits the functions of TNF in vitro and in vivo. With SAR441566 being studied in healthy volunteers we hope to deliver a more convenient orally bioavailable and effective treatment option for patients suffering with chronic autoimmune diseases compared to established biologic drugs targeting TNF.https://www.frontiersin.org/articles/10.3389/fphar.2022.1037983/fullTNFrheumatoid arthritissmall moleculeTNF trimerimmunogenicity |
| spellingShingle | Alexander Vugler James O’Connell Mai Anh Nguyen Dietmar Weitz Thomas Leeuw Elizabeth Hickford Alexander Verbitsky Xiaoyou Ying Markus Rehberg Bruce Carrington Mark Merriman Andrew Moss Jean-Marie Nicholas Phil Stanley Sara Wright Tim Bourne Yann Foricher Zhaoning Zhu Daniel Brookings Helen Horsley Jag Heer Laurent Schio Matthias Herrmann Srinivas Rao Markus Kohlmann Peter Florian An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis Frontiers in Pharmacology TNF rheumatoid arthritis small molecule TNF trimer immunogenicity |
| title | An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis |
| title_full | An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis |
| title_fullStr | An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis |
| title_full_unstemmed | An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis |
| title_short | An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis |
| title_sort | orally available small molecule that targets soluble tnf to deliver anti tnf biologic like efficacy in rheumatoid arthritis |
| topic | TNF rheumatoid arthritis small molecule TNF trimer immunogenicity |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1037983/full |
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