Protein Kinases: Drug Targets for Immunological Disorders




Protein kinases play a major role in cellular activation processes, including signal transduction by diverse immunoreceptors. Given their roles in cell growth and death and in the production of inflammatory mediators, targeting kinases has proven to be an effective treatment strategy, initially as anticancer therapies, but shortly thereafter in immune-mediated diseases. Herein, we provide an overview of the status of small molecule inhibitors specifically generated to target protein kinases relevant to immune cell function, with an emphasis on those approved for the treatment of immune-mediated diseases. The development of inhibitors of Janus kinases that target cytokine receptor signalling has been a particularly active area, with Janus kinase inhibitors being approved for the treatment of multiple autoimmune and allergic diseases as well as COVID-19. In addition, TEC family kinase inhibitors (including Bruton's tyrosine kinase inhibitors) targeting antigen receptor signaling have been approved for haematological malignancies and graft versus host disease. This experience provides multiple important lessons regarding the importance (or not) of selectivity and the limits to which genetic information informs efficacy and safety. Many new agents are being generated, along with new approaches for targeting kinases.




The extraordinary advances in the basic science of immunology have provided therapeutic approaches that have revolutionized outcomes in patients with inflammatory and immune-mediated diseases. These include numerous successful therapeutic monoclonal antibodies and engineered recombinant cytokine receptors. Advances in deciphering the biochemical pathways of immune cell signaling similarly led to the generation of small molecule therapies that complement biologics. In this Review, we focus on protein kinase inhibitors and their use in immune-mediated and inflammatory disorders. Although this field has been reviewed numerous times, it moves extraordinarily quickly, with over 60 small molecule protein kinase inhibitors now approved and hundreds more in development6. We provide a brief history of targeted kinase inhibitors, which first emerged for the treatment of cancer. We then discuss how purposefully targeting signal transduction pathways used by major classes of immunoreceptors has led to the effective treatment of numerous immune-mediated disorders. We focus on Janus kinase (JAK) inhibitors as they comprise one of the most active and successful areas, but we also review the successful targeting of TEC family kinases and other emerging protein kinase drug targets. We compare the ways in which kinase inhibitors may be similar yet distinct from biologics targeting cells and cytokines, and we consider future approaches and opportunities in this field.

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