Allosteric TYK2 inhibition: redefining autoimmune disease therapy beyond JAK1-3 inhibitors
Summary: JAK inhibitors impact multiple cytokine pathways simultaneously, enabling high efficacy in treating complex diseases such as cancers and immune-mediated disorders. However, their broad reach also poses safety concerns, which have fuelled a demand for increasingly selective JAK inhibitors.De...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-11-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396423004061 |
| _version_ | 1797656119915577344 |
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| author | Lise Torp Jensen Kathrine E. Attfield Marc Feldmann Lars Fugger |
| author_facet | Lise Torp Jensen Kathrine E. Attfield Marc Feldmann Lars Fugger |
| author_sort | Lise Torp Jensen |
| collection | DOAJ |
| description | Summary: JAK inhibitors impact multiple cytokine pathways simultaneously, enabling high efficacy in treating complex diseases such as cancers and immune-mediated disorders. However, their broad reach also poses safety concerns, which have fuelled a demand for increasingly selective JAK inhibitors.Deucravacitinib, a first-in-class allosteric TYK2 inhibitor, represents a remarkable advancement in the field. Rather than competing at kinase domain catalytic sites as classical JAK1-3 inhibitors, deucravacitinib targets the regulatory pseudokinase domain of TYK2. It strikingly mirrors the functional effect of an evolutionary conserved naturally occurring TYK2 variant, P1104A, known to protect against multiple autoimmune diseases yet provide sufficient TYK2-mediated cytokine signalling required to prevent immune deficiency.The unprecedentedly high functional selectivity and efficacy-safety profile of deucravacitinib, initially demonstrated in psoriasis, combined with genetic support, and promising outcomes in early SLE clinical trials make this inhibitor ripe for exploration in other autoimmune diseases for which better, safe, and efficacious treatments are urgently needed. |
| first_indexed | 2024-03-11T17:24:45Z |
| format | Article |
| id | doaj.art-643fdd9584884ebb80fcd97b871d12a4 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-03-11T17:24:45Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-643fdd9584884ebb80fcd97b871d12a42023-10-19T04:22:21ZengElsevierEBioMedicine2352-39642023-11-0197104840Allosteric TYK2 inhibition: redefining autoimmune disease therapy beyond JAK1-3 inhibitorsLise Torp Jensen0Kathrine E. Attfield1Marc Feldmann2Lars Fugger3Department of Clinical Medicine, Aarhus University Hospital, Aarhus 8200, DenmarkNuffield Department of Clinical Neurosciences, Oxford Centre for Neuroinflammation, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UKNuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, The Kennedy Institute for Rheumatology, Botnar Research Institute, University of Oxford, Oxford OX3 7LD, UKDepartment of Clinical Medicine, Aarhus University Hospital, Aarhus 8200, Denmark; Nuffield Department of Clinical Neurosciences, Oxford Centre for Neuroinflammation, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK; MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; Corresponding author. Nuffield Department of Clinical Neurosciences, Oxford Centre for Neuroinflammation, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.Summary: JAK inhibitors impact multiple cytokine pathways simultaneously, enabling high efficacy in treating complex diseases such as cancers and immune-mediated disorders. However, their broad reach also poses safety concerns, which have fuelled a demand for increasingly selective JAK inhibitors.Deucravacitinib, a first-in-class allosteric TYK2 inhibitor, represents a remarkable advancement in the field. Rather than competing at kinase domain catalytic sites as classical JAK1-3 inhibitors, deucravacitinib targets the regulatory pseudokinase domain of TYK2. It strikingly mirrors the functional effect of an evolutionary conserved naturally occurring TYK2 variant, P1104A, known to protect against multiple autoimmune diseases yet provide sufficient TYK2-mediated cytokine signalling required to prevent immune deficiency.The unprecedentedly high functional selectivity and efficacy-safety profile of deucravacitinib, initially demonstrated in psoriasis, combined with genetic support, and promising outcomes in early SLE clinical trials make this inhibitor ripe for exploration in other autoimmune diseases for which better, safe, and efficacious treatments are urgently needed.http://www.sciencedirect.com/science/article/pii/S2352396423004061JAK inhibitorsTYK2Autoimmune diseaseDeucravacitinib |
| spellingShingle | Lise Torp Jensen Kathrine E. Attfield Marc Feldmann Lars Fugger Allosteric TYK2 inhibition: redefining autoimmune disease therapy beyond JAK1-3 inhibitors EBioMedicine JAK inhibitors TYK2 Autoimmune disease Deucravacitinib |
| title | Allosteric TYK2 inhibition: redefining autoimmune disease therapy beyond JAK1-3 inhibitors |
| title_full | Allosteric TYK2 inhibition: redefining autoimmune disease therapy beyond JAK1-3 inhibitors |
| title_fullStr | Allosteric TYK2 inhibition: redefining autoimmune disease therapy beyond JAK1-3 inhibitors |
| title_full_unstemmed | Allosteric TYK2 inhibition: redefining autoimmune disease therapy beyond JAK1-3 inhibitors |
| title_short | Allosteric TYK2 inhibition: redefining autoimmune disease therapy beyond JAK1-3 inhibitors |
| title_sort | allosteric tyk2 inhibition redefining autoimmune disease therapy beyond jak1 3 inhibitors |
| topic | JAK inhibitors TYK2 Autoimmune disease Deucravacitinib |
| url | http://www.sciencedirect.com/science/article/pii/S2352396423004061 |
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