Autoimmune disorders such as multiple sclerosis, psoriasis, and rheumatoid arthritis (RA), just to name a few, affect millions of people and have various contributing factors that lead to disease; some known and some unknown. These disorders occur due to the immune system’s failure to discriminate between self vs. foreign entities.
Janus Kinase 3 (JAK3) is a tyrosine kinase that activates cytokines which is just one type of protein involved in cellular functions that police and drive the immune response. Subsequently, a non-functioning JAK3 consequently changing protein expression levels can contribute to autoimmune disease.
JAK3 is primarily expressed in lymphocytes (type of immune cell-specific to blood and lymph tissue), whereas other JAK kinases are expressed more abundantly throughout the body, making it a perfect target for therapeutics.1
Furthermore, mutations in JAK3 have been associated with severe combined immunodeficiency (SCID), which severely impacts the immune response due to the impairment of both T cells and B cells.2 JAK3 is just one of several cytokine signaling enzymes that continue to be evaluated, especially in finding inhibitors to mitigate unhealthy immune responses such as autoimmune disorders and SCID.
JAK-STAT Signaling Pathway
Cytokines, including but not limited to IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, contribute to T-cell proliferation, differentiation, and development – vital to a proper immune response. Once a cytokine binds to an appropriate cell surface receptor, the associated JAK gets phosphorylated. A signal transducer and activator of transcription (STAT) protein associates lead to transcription of genes involved in several cellular functions such as the immune response. Inhibiting JAK3 in patients with immune response deficiencies could be beneficial since the role of JAK3 is essential in the JAK-STAT signaling pathway and, ultimately, the transcription of genes responsible for keeping us healthy.1
JAK3 Inhibitors and ADP Activity Assays
Researchers have been discovering new JAK modulators, including JAK3 inhibitors, specifically to combat autoimmune disorders and SCID. Specifically, Robinette et al. found that the JAK inhibitor, tofacitinib, and the specific JAK3 inhibitor, PF-06651600, decreased interferon-gamma production (IFNγ); a cytokine linked to autoimmune disease when not properly regulated.
Due to the diverse locations and specific functions of JAKs, it’s imperative to ensure therapies such as JAK3 inhibitors treat the intended pathology without unwanted consequences, adding to the challenges in drug discovery.
The Transcreener® ADP² Kinase Assay can detect enzymatic activity, Kinases, ATPases, and virtually any enzyme-producing ADP. The easy-to-use universal ADP assay limits the need for specific reagents, making it ideal for detecting JAK3 activity, follow-up SAR, and inhibitor selectivity profiling.
See how the Transcreener Assay works to measure JAK3 activity to screen for novel inhibitors.
- Elwood, F., Witter, D. J., Piesvaux, J., Kraybill, B., Bays, N., Alpert, C., … Dandliker, P. J. (2017). Evaluation of JAK3 biology in autoimmune disease using a highly selective, irreversible JAK3 inhibitor. Journal of Pharmacology and Experimental Therapeutics, 361(2), 229–244. https://doi.org/10.1124/jpet.116.239723
- Robinette, M. L., Cella, M., Telliez, J. B., Ulland, T. K., Barrow, A. D., Capuder, K., … Colonna, M. (2018). Jak3 deficiency blocks innate lymphoid cell development. Mucosal Immunology, 11(1), 50–60. https://doi.org/10.1038/mi.2017.38