Prevention of Organ Allograft Rejection by a Specific Janus Kinase 3 Inhibitor

Changelian, Paul S.; Flanagan, Mark E.; Ball, Douglas J.; Kent, Craig R.; Magnuson, Kelly S.; Martin, William H.; Rizzuti, Bonnie J.; Sawyer, Perry S.; Perry, Bret D.; Brissette, William H.; McCurdy, Sandra P.; Kudlacz, Elizabeth M.; Conklyn, Maryrose; Elliott, Eileen A.; Koslov, Erika R.; Fisher, Michael B.; Strelevitz, Timothy J.; Yoon, Kwansik; Whipple, David A.; Sun, Jianmin; Munchhof, Michael J.; Doty, John L.; Casavant, Jeffrey; Blumenkopf, Todd A.; Hines, Michael H.; Brown, Matthew F.; Lillie, Brett M.; Subramanyam, Chakrapani; Shang-Poa, Chang; Milici, Anthony J.; Beckius, Gretchen E.; Moyer, James D.; Su, Chunyan; Woodworth, Thasia; Gaweco, Anderson S.; Beals, Chan R.; Littman, Bruce H.; Fisher, Douglas A.; Smith, James F.; Zagouras, Panayiotis; Magna, Holly A.; Saltarelli, Mary; Johnson, Kimberly S.; Nelms, Linda; Etages, Shelley G. Des; Hayes, Lisa S.; Kawabata, Thomas T.; Finco‐Kent, Deborah; Baker, Deanna L.; Larson, Michael J.; Sing, Ming; Paniagua, Ricardo; Higgins, Julian P T; Holm, Bari; Reitz, Bruce A.; Zhou, Yong; Morris, Randall E.; O’Shea, John J.; Borie, Dominic C.

doi:10.1126/science.1087061

Cited by 631 publications

(439 citation statements)

References 18 publications

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“…Although CP-690,550 inhibits JAK-3, it also has an overlapping activity against JAK-1 and JAK-2 (15,16). This fact raises the question of whether inhibition of JAK-3 alone is sufficient to disrupt cytokine signaling and to result in amelioration of autoimmune disease pathology.…”

mentioning

confidence: 99%

Selective functional inhibition of JAK‐3 is sufficient for efficacy in collagen‐induced arthritis in mice

Lin

Hegen

Quadros

et al. 2010

Arthritis & Rheumatism

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Objective. All ␥-chain cytokines signal through JAK-3 and JAK-1 acting in tandem. We undertook this study to determine whether the JAK-3 selective inhibitor WYE-151650 would be sufficient to disrupt cytokine signaling and to ameliorate autoimmune disease pathology without inhibiting other pathways mediated by JAK-1, JAK-2, and Tyk-2.Methods. JAK-3 kinase selective compounds were characterized by kinase assay and JAK-3-dependent (interleukin-2 [IL-2]) and -independent (IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF]) cell-based assays measuring proliferation or STAT phosphorylation. In vivo, off-target signaling was measured by IL-22-and erythropoietin (EPO)-mediated models, while on-target signaling was measured by IL-2-mediated signaling. Efficacy of JAK-3 inhibitors was determined using delayed-type hypersensitivity (DTH) and collagen-induced arthritis (CIA) models in mice.Results. In vitro, WYE-151650 potently suppressed IL-2-induced STAT-5 phosphorylation and cell proliferation, while exhibiting 10-29-fold less activity against JAK-3-independent IL-6-or GM-CSF-induced STAT phosphorylation. Ex vivo, WYE-151650 suppressed IL-2-induced STAT phosphorylation, but not IL-6-induced STAT phosphorylation, as measured in whole blood. In vivo, WYE-151650 inhibited JAK-3-mediated IL-2-induced interferon-␥ production and decreased the natural killer cell population in mice, while not affecting IL-22-induced serum amyloid A production or EPO-induced reticulocytosis. WYE-151650 was efficacious in mouse DTH and CIA models.Conclusion. In vitro, ex vivo, and in vivo assays demonstrate that WYE-151650 is efficacious in mouse CIA despite JAK-3 selectivity. These data question the need to broadly inhibit JAK-1-, JAK-2-, or Tyk-2-dependent cytokine pathways for efficacy.

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confidence: 99%

Selective functional inhibition of JAK‐3 is sufficient for efficacy in collagen‐induced arthritis in mice

Lin

Hegen

Quadros

et al. 2010

Arthritis & Rheumatism

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“…20,21,23 Another Jak inhibitor that preferentially inhibits Jak3 (the reported IC 50 of in vitro kinase inhibitory activity is for Jak3 1 nM, for Jak2 20 nM and for Jak1 100 nM) has been synthesized according to the published structure. 24 All inhibitors were reconstituted in DMSO to the suitable stock concentration and diluted shortly before the experiments to the final concentrations shown in the figures.…”

Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Inhibition of ALK enzymatic activity in T-cell lymphoma cells induces apoptosis and suppresses proliferation and STAT3 phosphorylation independently of Jak3

Marzec

Kasprzycka

Ptasznik

et al. 2005

Laboratory Investigation

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Aberrant expression of the ALK tyrosine kinase as a chimeric protein with nucleophosmin (NPM) and other partners plays a key role in malignant cell transformation of T-lymphocytes and other cells. Here we report that two small-molecule, structurally related, quinazoline-type compounds, WHI-131 and WHI-154, directly inhibit enzymatic activity of NPM/ALK as demonstrated by in vitro kinase assays using a synthetic tyrosine-rich oligopeptide and the kinase itself as the substrates. The inhibition of NPM/ALK activity resulted in malignant T cells in suppression of their growth, induction of apoptosis and inhibition of tyrosine phosphorylation of STAT3, the key effector of the NPM/ALK-induced oncogenesis. We also show that the STAT3 tyrosine phosphorylation is mediated in the malignant T cells by NPM/ALK independently of Jak3 kinase as evidenced by the presence of STAT3 phosphorylation in the NPM/ALK-transfected BaF3 cells that do not express detectable Jak3 and in the NPM/ALK-positive malignant T cells with either Jak3 activity impaired by a pan-Jak or Jak3-selective inhibitor or Jak3 expression abrogated by Jak3 siRNA. The above results represent the 'proof-ofprinciple' experiments with regard to the ALK enzymatic activity as an attractive therapeutic target in T-cell lymphomas and other malignancies that express the kinase in an active form. Laboratory Investigation (2005) 85, 1544-1554.

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“…12 The authors incubated ALK þ ALCL cells with this compound for 1 h and used Western blotting techniques to demonstrate that there was no significant change in pStat3 levels. Notably, the effect of this compound on Jak3/pJak3 levels was not shown in the manuscript.…”

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confidence: 99%

Jak3 contributes to the activation of ALK and Stat3 in ALK+ anaplastic large cell lymphoma

Amin

Lin

Lai

2006

Laboratory Investigation

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Prevention of Organ Allograft Rejection by a Specific Janus Kinase 3 Inhibitor

Cited by 631 publications

References 18 publications

Selective functional inhibition of JAK‐3 is sufficient for efficacy in collagen‐induced arthritis in mice

Selective functional inhibition of JAK‐3 is sufficient for efficacy in collagen‐induced arthritis in mice

Inhibition of ALK enzymatic activity in T-cell lymphoma cells induces apoptosis and suppresses proliferation and STAT3 phosphorylation independently of Jak3

Jak3 contributes to the activation of ALK and Stat3 in ALK+ anaplastic large cell lymphoma

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