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Key Event Title
Inhibition of JAK3
|Level of Biological Organization|
Key Event Components
|regulation of binding||tyrosine-protein kinase JAK3||decreased|
Key Event Overview
AOPs Including This Key Event
|All life stages||High|
Key Event Description
Janus tyrosine kinase (JAK) 3 is a member of the JAK family, is constitutively associated with the Box-1 region of the cytokine receptor intracellular domain, and becomes activated upon ligand-induced receptor dimerization (40-Stahl-1994).
To date, PF-06651600 is the only single isoform-selective JAK3 inhibitor to undergo a phase 2 clinical evaluation to treat rheumatoid arthritis. This compound inhibits JAK3 kinase activity with an IC50 of 33.1 nM but without activity (IC50 > 10000 nM) against JAK1, JAK2, or Tyrosine kinase (TYK)2 (7-Telliez-2016,41-Thorarensen-2017). RB1 has been also identified as a novel and highly selective JAK3 inhibitor, which blocks in vitro JAK3 kinase and functional activity in various cell types. When administered to mice orally, RB1 has been proven to mediate the JAK-Signal Transducer and Activator of Transcription (STAT) (JAK-STAT) pathway and reduce the clinical and microscopic manifestations of paw damage in collagen induced arthritis mice.
How It Is Measured or Detected
The enzymatic activities against JAK1, JAK2, JAK3, and TYK2 are tested by a Caliper Mobility Shift Assay. In the presence of an ATP concentration at Km for ATP for each JAK isoform, RB1 inhibited JAK3 kinase activity with an IC50 value of 40 nM without inhibiting JAK1, JAK2 or TYK2 (IC50 > 5000 nM) (42-Gianti-2015). PF-06651600 is also a potent JAK3-selective inhibitor which can inhibit the JAK3 kinase activity with an IC50 of 33.1 nM but without activity (IC50>10 000 nM) against JAK1, JAK2, and TYK2. PF-06651600 inhibits the phosphorylation of STAT5 elicited by IL-2, IL-4, IL-7, and IL-15 with IC50 values of 244, 340, 407, and 266 nM, respectively (7-Telliez-2016).
Domain of Applicability
JAKs are a family of nonreceptor protein tyrosine kinases that are critical for cytokine-receptor-binding-triggered signal transduction through STAT to the nuclei of cells. The JAK family consists of four members: JAK1, JAK2, JAK3 and TYK. In mammals JAK1, JAK2 and TYK2 are ubiquitously expressed. In contrast, the expression of JAK3 is more restricted: it is predominantly expressed in haematopoietic cells and is highly regulated with cell development and activation (43-Xu-1996,44-Gaffen-1995). JAK3 is solely activated by type I cytokine receptors featuring a common γ-chain (γc) subunit that are activated by IL-2, IL-4, IL-7, IL-9, IL-15, and IL-7 (12-Peschon-1994). Mutations in either the γ-chain or JAK3 have been identified as a cause of severe combined immunodeficiency disease (SCID) in humans, which manifests as a depletion of T, B, and natural killer (NK) cells with no other defects (45-Darnell-1997,46-Decker-1997).
Loss-of-function mutations in the tyrosine kinase JAK3 cause autosomal recessive SCID. Defects in this form of SCID are restricted to the immune system, which led to the development of the immunosuppressive JAK inhibitors.
Evidence for Perturbation by Stressor
Overview for Molecular Initiating Event
7. Telliez, J. B., Dowty, M. E., Wang, L., Jussif, J., Lin, T., Li, L., Moy, E., Balbo, P., Li, W., Zhao, Y., Crouse, K., Dickinson, C., Symanowicz, P., Hegen, M., Banker, M. E., Vincent, F., Unwalla, R., Liang, S., Gilbert, A. M., Brown, M. F., Hayward, M., Montgomery, J., Yang, X., Bauman, J., Trujillo, J. I., Casimiro-Garcia, A., Vajdos, F. F., Leung, L., Geoghegan, K. F., Quazi, A., Xuan, D., Jones, L., Hett, E., Wright, K., Clark, J. D., and Thorarensen, A. (2016) Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol 11, 3442-3451
12. Peschon, J. J., Morrissey, P. J., Grabstein, K. H., Ramsdell, F. J., Maraskovsky, E., Gliniak, B. C., Park, L. S., Ziegler, S. F., Williams, D. E., Ware, C. B., Meyer, J. D., and Davison, B. L. (1994) Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med 180, 1955-1960
40. Stahl, N., Boulton, T. G., Farruggella, T., Ip, N. Y., Davis, S., Witthuhn, B. A., Quelle, F. W., Silvennoinen, O., Barbieri, G., Pellegrini, S., and et al. (1994) Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science 263, 92-95
41. Thorarensen, A., Dowty, M. E., Banker, M. E., Juba, B., Jussif, J., Lin, T., Vincent, F., Czerwinski, R. M., Casimiro-Garcia, A., Unwalla, R., Trujillo, J. I., Liang, S., Balbo, P., Che, Y., Gilbert, A. M., Brown, M. F., Hayward, M., Montgomery, J., Leung, L., Yang, X., Soucy, S., Hegen, M., Coe, J., Langille, J., Vajdos, F., Chrencik, J., and Telliez, J. B. (2017) Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop -2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans. J Med Chem 60, 1971-1993
42. Gianti, E., and Zauhar, R. J. (2015) An SH2 domain model of STAT5 in complex with phospho-peptides define "STAT5 Binding Signatures". J Comput Aided Mol Des 29, 451-470
43. Xu, B. C., Wang, X., Darus, C. J., and Kopchick, J. J. (1996) Growth hormone promotes the association of transcription factor STAT5 with the growth hormone receptor. J Biol Chem 271, 19768-19773
44. Gaffen, S. L., Lai, S. Y., Xu, W., Gouilleux, F., Groner, B., Goldsmith, M. A., and Greene, W. C. (1995) Signaling through the interleukin 2 receptor beta chain activates a STAT-5-like DNA-binding activity. Proc Natl Acad Sci U S A 92, 7192-7196
45. Darnell, J. E., Jr. (1997) STATs and gene regulation. Science 277, 1630-1635
46. Decker, T., Kovarik, P., and Meinke, A. (1997) GAS elements: a few nucleotides with a major impact on cytokine-induced gene expression. J Interferon Cytokine Res 17, 121-134