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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 that is constitutively associated with the Box-1 region of the cytokine receptor intracellular domain. JAK3 is activated upon ligand-induced receptor dimerization (Stahl, et al. 1994).
The PF-06651600 selective JAK3 inhibitor is undergoing phase 2 clinical evaluation for use in treating rheumatoid arthritis. This compound inhibits JAK3 kinase activity with an IC50 of 33.1 nM (IC50 > 10000 nM). It lacks activity against JAK1, JAK2, or TYK2 (Telliez, et al. 2016, Thorarensen, et al. 2017). The RB1 novel and highly selective JAK3 inhibitor blocks JAK3 kinase in vitro and abrogates functional activity in various cell types (Pei, et al. 2018). When orally administered to mice, RB1 mediate the JAK-STAT pathway and reduces the clinical and microscopic manifestations of paw damage in collagen-induced arthritis mice.
How It Is Measured or Detected
Enzymatic activities against JAK1, JAK2, JAK3, and TYK2 were examined using 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) (Gianti and Zauhar 2015). The PF-06651600 JAK3 inhibitor displays potent inhibitory activity with an IC50 of 33.1 nM (IC50>10 000 nM), with no activity against JAK1, JAK2, and TYK2. PF-06651600 inhibits the phosphorylation of STAT5 elicited by IL-2, IL-4, IL-7, and IL-15 with an IC50 of 244, 340, 407, and 266 nM, respectively (Telliez, et al. 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. In mammals, the JAK1, JAK2, and TYK2 kinases are ubiquitously expressed. In contrast, the expression of JAK3 is more restricted. It is predominantly expressed in hematopoietic cells and is highly regulated by cell development and activation (Gaffen, et al. 1995, Xu, et al. 1996). JAK3 is solely activated by type I cytokine receptors, featuring a common γ-chain subunit that is activated by IL-2, IL-4, IL-7, IL-9, IL-15, and IL-7 (Peschon, et al. 1994). Mutations in either the γ chain or JAK3 have been identified as a cause of SCID in humans, which manifests as a depletion of T, B, and NK cells with no other defects (Darnell 1997, Decker, et al. 1997).
Loss-of-function mutations in JAK3 cause autosomal recessive SCID. Defects in this form of SCID are restricted to the immune system, which leads to the development of immunosuppressive JAK inhibitors.
Darnell JE, Jr. 1997. STATs and gene regulation. Science 277:1630-1635.
Decker T, Kovarik P, Meinke A. 1997. GAS elements: a few nucleotides with a major impact on cytokine-induced gene expression. J Interferon Cytokine Res 17:121-134. DOI: 10.1089/jir.1997.17.121.
Gaffen SL, Lai SY, Xu W, Gouilleux F, Groner B, Goldsmith MA, Greene WC. 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.
Gianti E, Zauhar RJ. 2015. An SH2 domain model of STAT5 in complex with phospho-peptides define "STAT5 Binding Signatures". J Comput Aided Mol Des 29:451-470. DOI: 10.1007/s10822-015-9835-6.
Pei H, He L, Shao M, Yang Z, Ran Y, Li D, Zhou Y, Tang M, Wang T, Gong Y, Chen X, Yang S, Xiang M, Chen L. 2018. Discovery of a highly selective JAK3 inhibitor for the treatment of rheumatoid arthritis. Sci Rep 8:5273. DOI: 10.1038/s41598-018-23569-y.
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Telliez JB, Dowty ME, 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 ME, Vincent F, Unwalla R, Liang S, Gilbert AM, Brown MF, Hayward M, Montgomery J, Yang X, Bauman J, Trujillo JI, Casimiro-Garcia A, Vajdos FF, Leung L, Geoghegan KF, Quazi A, Xuan D, Jones L, Hett E, Wright K, Clark JD, 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. DOI: 10.1021/acschembio.6b00677.
Thorarensen A, Dowty ME, Banker ME, Juba B, Jussif J, Lin T, Vincent F, Czerwinski RM, Casimiro-Garcia A, Unwalla R, Trujillo JI, Liang S, Balbo P, Che Y, Gilbert AM, Brown MF, Hayward M, Montgomery J, Leung L, Yang X, Soucy S, Hegen M, Coe J, Langille J, Vajdos F, Chrencik J, Telliez JB. 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. DOI: 10.1021/acs.jmedchem.6b01694.
Xu BC, Wang X, Darus CJ, Kopchick JJ. 1996. Growth hormone promotes the association of transcription factor STAT5 with the growth hormone receptor. J Biol Chem 271:19768-19773.