JAK inhibitor selectivity: new opportunities, better drugs?

Autor: Virtanen A; Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.; Institute of Biotechnology, HiLIFE Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland., Spinelli FR; Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari-Reumatologia, Sapienza Universitá di Roma, Rome, Italy., Telliez JB; Inflammation and Immunology, Pfizer, Cambridge, MA, USA., O'Shea JJ; Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA., Silvennoinen O; Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.; Institute of Biotechnology, HiLIFE Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.; Fimlab laboratories, Tampere, Finland., Gadina M; Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA. gadinama@nih.gov.
Jazyk: angličtina
Zdroj: Nature reviews. Rheumatology [Nat Rev Rheumatol] 2024 Oct; Vol. 20 (10), pp. 649-665. Date of Electronic Publication: 2024 Sep 09.
DOI: 10.1038/s41584-024-01153-1
Abstrakt: Cytokines function as communication tools of the immune system, serving critical functions in many biological responses and shaping the immune response. When cytokine production or their biological activity goes awry, the homeostatic balance of the immune response is altered, leading to the development of several pathologies such as autoimmune and inflammatory disorders. Cytokines bind to specific receptors on cells, triggering the activation of intracellular enzymes known as Janus kinases (JAKs). The JAK family comprises four members, JAK1, JAK2, JAK3 and tyrosine kinase 2, which are critical for intracellular cytokine signalling. Since the mid-2010s multiple JAK inhibitors have been approved for inflammatory and haematological indications. Currently, approved JAK inhibitors have demonstrated clinical efficacy; however, improved selectivity for specific JAKs is likely to enhance safety profiles, and different strategies have been used to accomplish enhanced JAK selectivity. In this update, we discuss the background of JAK inhibitors, current approved indications and adverse effects, along with new developments in this field. We address the issue of JAK selectivity and its relevance in terms of efficacy, and describe new modalities of JAK targeting, as well as new aspects of JAK inhibitor action.
(© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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