Protein kinases: drug targets for immunological disorders

Abstract

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 signalling 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.

Soquelitinib, A Selective Inhibitor of Interleukin-2-Inducible T Cell Kinase (ITK), is Active in Several Murine Models of T Cell-Mediated Inflammatory Disease

“…Indeed, in an ongoing clinical trial with SQL for the treatment of relapsed, refractory T cell lymphoma, we have demonstrated anti-tumor activity without an increased incidence of opportunistic infection (NCT03952078) 30 . The development of selective and effective inhibitors targeting specific kinases such as BTK, JAKs, and EGFR has revolutionized the treatment of numerous diseases 31 . In the aGVHD model, SQL reduces the activation and proliferation of T cells 9 (see also Figure 6A).…”

The USP7-STAT3-granzyme-Par-1 axis regulates allergic inflammation by promoting differentiation of IL-5-producing Th2 cells

“…Blockade of one molecule in the USP7-STAT3-granzyme-Par-1 axis is a potential therapeutic target against chronic allergic diseases. Indeed, the inhibition of Janus kinases, which are located upstream of the STAT3 signaling pathway, has already been applied to various immune-related diseases ( 43 ). However, the systemic inhibition of these molecules should be confirmed to determine whether or not they cause major side effects, given the intimate involvement of these molecules in many critical biological pathways in humans.…”

Integrating the analysis of human biopsies using post‐translational modifications proteomics

“…Phosphorylation of amino acids is a common PTM and can provide insight into signaling cascades, gene expression, and the activity state of kinases or other enzymes (Castelo‐Soccio et al, 2023 ). Phosphorylation generally occurs on residues that have a hydroxyl group present on their side chain such as serine, tyrosine, and threonine, but other residues can also be phosphorylated (Ubersax & Ferrell, 2007 ).…”

“…These chemical modifications can alter protein localization and function, making PTM analysis vital in understanding proteomic signatures as biomarkers in human tissue (Klein et al, 2018 ; Mainoli et al, 2020 ). However, profiling PTMs is uniquely challenging given their transient nature and relatively low abundance (Castelo‐Soccio et al, 2023 ; Wang et al, 2021 ). The emergence of sensitive liquid chromatography and tandem mass spectrometry (LC–MS/MS) techniques that enrich selective PTMs has generated crucial knowledge to better understand their roles in homeostasis and disease.…”