Kinases in Autoimmune Diseases: Key Advances and Therapeutic Directions
Sino Biological, Inc.
Global Leader in Recombinant Technology for the Life Sciences
Kinases have emerged as pivotal therapeutic targets in autoimmune diseases due to their central role in immune cell signaling and dysregulated inflammatory pathways[1]. These enzymes regulate cellular responses through phosphorylation, modulating processes from cytokine production to immune cell activation. The development of inhibitors to JAK-STAT, BTK, SYK and a few other kinases has revolutionized treatment paradigms, offering targeted strategies with improved efficacy over broad immunosuppressants[2]. Currently, the FDA has approved multiple kinase inhibitors (e.g., JAK, SYK inhibitors) for the treatment of various autoimmune diseases including rheumatoid arthritis, multiple sclerosis, and psoriasis. SignalChem Biotech, now part of Sino Biological, offers a vast selection of kinases involved in autoimmune diseases. These tools are crucial for advancing research into more effective targeted therapies for autoimmune diseases.
Physiological and Pathological Roles
The JAK-STAT (Janus Kinase-Signal Transducer and Activator of Transcription) pathway calibrates T-cell differentiation, B-cell survival, and innate defenses[3]. Hyper-responsive JAK–STAT signaling promotes Th1/Th17 skewing, B-cell autoantibody secretion and interferon signatures in autoimmune conditions like rheumatoid arthritis (RA), psoriasis and systemic lupus erythematosus (SLE)[3]. Bruton’s Tyrosine Kinase (BTK) drives B cell receptor signaling and autoantibody production, implicated in systemic SLE and multiple sclerosis (MS)[2,4]. Excess BTK activity sustains autoreactive B-cell survival and myeloid antigen presentation. Spleen Tyrosine Kinase (SYK) integrates signals from Fcγ receptors and B-cell receptor (BCR) signaling, amplifying inflammatory responses like immune thrombocytopenia (ITP)[2]. IRAK4 and MAPK p38α act downstream of IL-1/TLR (toll like receptor) and stress receptors, respectively, to trigger NF-κB and inflammatory gene transcription. PI3Kδ overactivation causes immunodeficiency with autoimmunity. Aberrant mTOR signaling drives T-cell exhaustion and fibrotic pathways in systemic sclerosis[5]. Other emerging kinase targets include Rho-associated kinases (ROCKs) that regulate immune cell migration and fibrosis with promise in preclinical models of scleroderma and lupus nephritis[6], and TPL2 that mediates IL-17 signaling, a key pathway in psoriasis and ankylosing spondylitis[1]. Figure 1 summarizes major druggable inflammatory pathways and downstream kinases implicated in human disease, highlighting drugs that are currently being clinically evaluated or already approved.
Figure 1[1]. Major druggable inflammatory pathways and downstream kinases implicated in human disease, highlighting drugs that are currently being clinically evaluated or already approved. All biologics that are included have mostly been evaluated in phase II trials and beyond. All small-molecule kinase inhibitors have been evaluated in phase I and beyond.
From Bench to Bedside
Kinase inhibitors interrupt the intracellular signaling cascades that drive autoimmune inflammation, primarily by blocking cytokine signaling, modulating immune cell function, and reducing the pathological immune responses that underlie autoimmune diseases. Over 10 kinase inhibitors are approved by FDA for autoimmune diseases. Representative drugs in recent years are summarized in Table 1:
Table 1. Representative Molecules and FDA-approved Protein Kinases Drugs
Table 2. More Protein Kinases in Preclinical and Clinical Studies
Disease Abbreviations
Although kinase inhibitors have been extensively investigated, some candidates still carry class-specific risks that may impose safety challenges, such as increased susceptibility to herpes zoster and respiratory infections due to immunosuppression[7], thromboembolism seen in JAK inhibitors like tofacitinib that show elevated venous thrombosis risk[7], malignancies like non-melanoma skin cancers and lymphoma that likely correlate with impaired immune surveillance after long-term use[7], and hepatotoxicity resulting from SYK inhibitors like fostamatinib[2]. Dose optimization and biomarker-guided therapy (e.g., C-reactive protein levels) can help balance efficacy and safety[2,7].
Application in Research
Recombinant kinases from Sino Biological/SignalChem have been widely utilized for autoimmune disease studies. PIM1 is a member of the serine/threonine protein kinase family. It is involved in many biological events, such as cell survival, cell cycle progression, cell proliferation, and cell migration, and has been widely studied in malignant diseases[8]. Active GST-tagged PIM1 (Cat#: P35-10G) was used by Cen et al[9] for investigation of the mechanism that Pim-1 kinase increases the level of Skp2 through phosphorylation of multiple sites on this protein (Figure 2). Recent researches have shown that PIM1 acts as a key regulator in autoimmune diseases by promoting inflammatory signaling, supporting the survival and activation of immune cells, and disrupting the balance between pro-inflammatory and regulatory immune mechanisms[10–12]. Its inhibition represents a promising strategy for treating a range of autoimmune and inflammatory disorders.
Figure 2. Using GST-PIM1 (Cat#: P35-10G), mutation of either Ser64 or Ser72 to Ala significantly decreased Skp2 phosphorylation, suggesting that Ser64 and/or Ser72 might be a PIM1 target. Thr417 mutation also presented notable abolished Skp2 phosphorylation. However, a complete understanding of the relationship between these sites requires further studies[9].
RIPK1 (Receptor-Interacting Protein Kinase 1) is a central regulator of cell death (apoptosis and necroptosis) and inflammation, playing a pivotal role in immune homeostasis and the pathogenesis of autoimmune diseases[13]. Riebeling et al used recombinant human RIPK1 (Cat#: R07-11G) to prove that the aromatic antiepileptic and FDA-approved drug primidone (Liskantin®) is a potent inhibitor of RIPK1 activation in vitro and in a murine model of TNFα-induced shock, which mimics the hyperinflammatory state of cytokine release syndrome. Inhibition of RIPK1 kinase activity has been shown to be protective in preclinical models of autoimmunity[14].
Figure 3. The kinase activity of recombinant human RIPK1 (Cat#: R07-11G) was measured by ADP-Glo™ Kinase Assay to reveal that primidone is an effective kinase inhibitor of RIPK1 (RLU = relative light units). In addition, Nec-1s (a confirmed kinase inhibitor of RIPK1) and GSK’872 (a specific kinase inhibitor of RIPK3) served as controls. The graph shows the mean ± SD of three independent experiments[13].
Using GST-PKCθ (Cat#: P74-10G) and GST-IKKβ proteins (Cat#: I03-18G), Chuang et al. demonstrated the binding of AhR to PKCθ protein in vitro and the direct interaction between IKKβ and RORγt by pull-down assays, respectively[15] (Figure 4). Their study revealed a critical role of the GLK-PKCθ/IKKβ-AhR/RORγt pathway in the pathogenesis of IL-17A-mediated autoimmune diseases[15].
Figure 4. (A) In vitro binding assays of purified HA-tagged AhR and GST-tagged PKCθ proteins. (B) Direct interaction between recombinant proteins of RORγt and IKKβ. GST or His pulldown assays of purified His-tagged RORγt and GST-tagged IKKβ proteins. Panels adopted from Reference[15].
Research Advancements and Future Outlook
Second-generation inhibitors like deucravacitinib (TYK2) exploit allosteric binding to enhance specificity, reducing off-target JAK inhibition[2,7]. BTK degraders, such as NX-2127, offer prolonged suppression of B cell activation in SLE models[7]. Other novel therapeutic avenues include: Fasudil, as ROCK inhibitors, ameliorates fibrosis in scleroderma by blocking TGF-β signaling; combination therapies like JAK inhibitors paired with biologics (e.g., IL-23 blockers) show synergistic effects in psoriasis[1,4]. More selective inhibitors targeting the p38α-MK2 axis are under investigation and may overcome previous limitations[16,17]. Nanocarrier systems enhance localized drug penetration in cutaneous lupus, minimizing systemic exposure[4]. Genetic profiling (e.g., TYK2 polymorphisms) and cytokine signatures (IL-6, IFN-γ) may predict treatment response, enabling personalized regimens[2,7]. Trials exploring kinase inhibitors in neuromyelitis optica and IgG4-related disease also highlight expanding indications[2,7].
References
1. Zarrin, A. A., Bao, K., Lupardus, P. & Vucic, D. Kinase inhibition in autoimmunity and inflammation. Nature Reviews Drug Discovery vol. 20 39–63 Preprint at https://doi.org/10.1038/s41573-020-0082-8 (2021).
2. Patterson, H., Nibbs, R., Mcinnes, I. & Siebert, S. Protein kinase inhibitors in the treatment of inflammatory and autoimmune diseases. Clinical and Experimental Immunology vol. 176 1–10 Preprint at https://doi.org/10.1111/cei.12248 (2014).
3. Castelo-Soccio, L. et al. Protein kinases: drug targets for immunological disorders. Nature Reviews Immunology 2023 23:12 23, 787–806 (2023).
4. Szilveszter, K. P., Németh, T. & Mócsai, A. Tyrosine kinases in autoimmune and inflammatory skin diseases. Frontiers in Immunology vol. 10 Preprint at https://doi.org/10.3389/fimmu.2019.01862 (2019).
5. Chi, H. Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol 12, 325–338 (2012).
6. Pernis, A. B., Ricker, E., Weng, C. H., Rozo, C. & Yi, W. Rho kinases in autoimmune diseases. Annu Rev Med 67, 355–374 (2016).
7. Castelo-Soccio, L. et al. Protein kinases: drug targets for immunological disorders. Nature Reviews Immunology vol. 23 787–806 Preprint at https://doi.org/10.1038/s41577-023-00877-7 (2023).
8. Zippo, A., De Robertis, A., Serafini, R. & Oliviero, S. PIM1-dependent phosphorylation of histone H3 at serine 10 is required for MYC-dependent transcriptional activation and oncogenic transformation. Nat Cell Biol 9, 932–944 (2007).
9. Cen, B. et al. Regulation of Skp2 Levels by the Pim-1 Protein Kinase. J Biol Chem 285, 29128 (2010).
10. Yang, X. et al. PIM1 signaling in immunoinflammatory diseases: an emerging therapeutic target. Front Immunol 15, 1443784 (2024).
11. Fu, R. et al. Pim-1 as a Therapeutic Target in Lupus Nephritis. Arthritis & Rheumatology 71, 1308–1318 (2019).
12. Baek, H. S., Kim, N., Park, J. W., Kwon, T. K. & Kim, S. The role of Pim-1 kinases in inflammatory signaling pathways. Inflammation Research 73, 1671–1685 (2024).
13. Riebeling, T. et al. Primidone blocks RIPK1-driven cell death and inflammation. Cell Death & Differentiation 2020 28:5 28, 1610–1626 (2020).
14. Degterev, A., Ofengeim, D. & Yuan, J. Targeting RIPK1 for the treatment of human diseases. Proc Natl Acad Sci U S A 116, 9714 (2019).
15. Chuang, H. C., Tsai, C. Y., Hsueh, C. H. & Tan, T. H. GLK-IKK signaling induces dimerization and translocation of the AhR-RORt complex in IL-17A induction and autoimmune disease. Sci Adv 4, 5401–5413 (2018).
16. Wang, C. et al. Selective inhibition of the p38α MAPK–MK2 axis inhibits inflammatory cues including inflammasome priming signals. Journal of Experimental Medicine 215, 1315–1325 (2018).
17. Ganguly, P., Macleod, T., Wong, C., Harland, M. & McGonagle, D. Revisiting p38 Mitogen-Activated Protein Kinases (MAPK) in Inflammatory Arthritis: A Narrative of the Emergence of MAPK-Activated Protein Kinase Inhibitors (MK2i). Pharmaceuticals 16, 1286 (2023).