Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Prevention of Organ Allograft Rejection by a Specific Janus Kinase 3 Inhibitor
Paul S. Changelian,1*Mark E. Flanagan,1Douglas J. Ball,2Craig R. Kent,1Kelly S. Magnuson,1William H. Martin,1Bonnie J. Rizzuti,1Perry S. Sawyer,1Bret D. Perry,1William H. Brissette,1Sandra P. McCurdy,1Elizabeth M. Kudlacz,1Maryrose J. Conklyn,1Eileen A. Elliott,1Erika R. Koslov,1Michael B. Fisher,3Timothy J. Strelevitz,3Kwansik Yoon,3David A. Whipple,1Jianmin Sun,1Michael J. Munchhof,1John L. Doty,1Jeffrey M. Casavant,1Todd A. Blumenkopf,1Michael Hines,1Matthew F. Brown,1Brett M. Lillie,1Chakrapani Subramanyam,1Chang Shang-Poa,1Anthony J. Milici,1Gretchen E. Beckius,1James D. Moyer,1Chunyan Su,1Thasia G. Woodworth,1Anderson S. Gaweco,1Chan R. Beals,1Bruce H. Littman,1Douglas A. Fisher,1James F. Smith,1Panayiotis Zagouras,4Holly A. Magna,4Mary J. Saltarelli,4Kimberly S. Johnson,4Linda F. Nelms,2Shelley G. Des Etages,4Lisa S. Hayes,4Thomas T. Kawabata,2Deborah Finco-Kent,2Deanna L. Baker,2Michael Larson,5Ming-Sing Si,5Ricardo Paniagua,5John Higgins,6Bari Holm,5Bruce Reitz,5Yong-Jie Zhou,7Randall E. Morris,5John J. O'Shea,7Dominic C. Borie5*
Because of its requirement for signaling by multiple cytokines,Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression.We report the development of a specific, orally active inhibitorof JAK3, CP-690,550, that significantly prolongedsurvival ina murine model of heart transplantation and in cynomolgus monkeysreceiving kidney transplants. CP-690,550 treatment was not associatedwithhypertension, hyperlipidemia, or lymphoproliferative disease.On the basis of these preclinical results, we believe JAK3 blockadeby CP-690,550 has potential for therapeutically desirable immunosuppressionin human organ transplantation andin other clinical settings.
1 Immunology Group, Department of Antibacterials and Immunology, Pfizer Global Researchand Development, Groton, CT 06340, USA. 2 Department of Drug Safety Evaluation, Pfizer Global Researchand Development, Groton, CT 06340, USA. 3 Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Researchand Development, Groton, CT 06340, USA. 4 Department of Genomic and Proteomic Sciences, Pfizer Global Researchand Development, Groton, CT 06340, USA. 5 Transplantation Immunology Laboratory, Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA. 6 Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. 7 Molecular Immunology and Inflammation Branch, National Institutes of Health, Bethesda, MD 20892, USA.
* To whom correspondence should be addressed. E-mail: paul_s_changelian{at}groton.pfizer.com (P.S.C.); dborie{at}stanford.edu (D.C.B.)
Effect of CP-690,550, an Orally Active Janus Kinase Inhibitor, on Renal Function in Healthy Adult Volunteers.
N. Lawendy, S. Krishnaswami, R. Wang, D. Gruben, C. Cannon, S. Swan, and G. Chan (2009)
J. Clin. Pharmacol.
49, 423-429
|Abstract »|Full Text »|PDF »
Signalling, inflammation and arthritis: Crossed signals: the role of interleukin-15 and -18 in autoimmunity.
H. P. Carroll, V. Paunovic, and M. Gadina (2008)
Rheumatology
47, 1269-1277
|Abstract »|Full Text »|PDF »
{gamma}c-Signaling Cytokines Induce a Regulatory T Cell Phenotype in Malignant CD4+ T Lymphocytes.
M. Kasprzycka, Q. Zhang, A. Witkiewicz, M. Marzec, M. Potoczek, X. Liu, H. Y. Wang, M. Milone, S. Basu, J. Mauger, et al. (2008)
J. Immunol.
181, 2506-2512
|Abstract »|Full Text »|PDF »
IL-7 Activates the Phosphatidylinositol 3-Kinase/AKT Pathway in Normal Human Thymocytes but Not Normal Human B Cell Precursors.
S. E. Johnson, N. Shah, A. A. Bajer, and T. W. LeBien (2008)
J. Immunol.
180, 8109-8117
|Abstract »|Full Text »|PDF »
Signalling, inflammation and arthritis: Crossed signals: the role of interleukin (IL)-12, -17, -23 and -27 in autoimmunity.
V. Paunovic, H. P. Carroll, K. Vandenbroeck, and M. Gadina (2008)
Rheumatology
47, 771-776
|Abstract »|Full Text »|PDF »
Phosphorylation of Human Jak3 at Tyrosines 904 and 939 Positively Regulates Its Activity.
H. Cheng, J. A. Ross, J. A. Frost, and R. A. Kirken (2008)
Mol. Cell. Biol.
28, 2271-2282
|Abstract »|Full Text »|PDF »
Differential Effects of Interleukin-2 and Interleukin-15 versus Interleukin-21 on CD4+ Cutaneous T-Cell Lymphoma Cells.
M. Marzec, K. Halasa, M. Kasprzycka, M. Wysocka, X. Liu, J. W. Tobias, D. Baldwin, Q. Zhang, N. Odum, A. H. Rook, et al. (2008)
Cancer Res.
68, 1083-1091
|Abstract »|Full Text »|PDF »
RNAi screening of the tyrosine kinome identifies therapeutic targets in acute myeloid leukemia.
J. W. Tyner, D. K. Walters, S. G. Willis, M. Luttropp, J. Oost, M. Loriaux, H. Erickson, A. S. Corbin, T. O'Hare, M. C. Heinrich, et al. (2008)
Blood
111, 2238-2245
|Abstract »|Full Text »|PDF »
IL-2- and IL-15-induced activation of the rapamycin-sensitive mTORC1 pathway in malignant CD4+ T lymphocytes.
M. Marzec, X. Liu, M. Kasprzycka, A. Witkiewicz, P. N. Raghunath, M. El-Salem, E. Robertson, N. Odum, and M. A. Wasik (2008)
Blood
111, 2181-2189
|Abstract »|Full Text »|PDF »
The specificity of JAK3 kinase inhibitors.
P. S. Changelian, D. Moshinsky, C. F. Kuhn, M. E. Flanagan, M. J. Munchhof, T. M. Harris, J. L. Doty, J. Sun, C. R. Kent, K. S. Magnuson, et al. (2008)
Blood
111, 2155-2157
|Abstract »|Full Text »|PDF »
PF00299804, an Irreversible Pan-ERBB Inhibitor, Is Effective in Lung Cancer Models with EGFR and ERBB2 Mutations that Are Resistant to Gefitinib.
J. A. Engelman, K. Zejnullahu, C.-M. Gale, E. Lifshits, A. J. Gonzales, T. Shimamura, F. Zhao, P. W. Vincent, G. N. Naumov, J. E. Bradner, et al. (2007)
Cancer Res.
67, 11924-11932
|Abstract »|Full Text »|PDF »
Kaempferol Inhibits IL-4-Induced STAT6 Activation by Specifically Targeting JAK3.
J. R. Cortes, M. Perez-G, M. D. Rivas, and J. Zamorano (2007)
J. Immunol.
179, 3881-3887
|Abstract »|Full Text »|PDF »
Abrogation of Signal Transducer and Activator of Transcription 3 Reactivation after Src Kinase Inhibition Results in Synergistic Antitumor Effects.
F. M. Johnson, B. Saigal, H. Tran, and N. J. Donato (2007)
Clin. Cancer Res.
13, 4233-4244
|Abstract »|Full Text »|PDF »
The Synthetic Triterpenoid CDDO-Imidazolide Suppresses STAT Phosphorylation and Induces Apoptosis in Myeloma and Lung Cancer Cells..
K. Liby, N. Voong, C. R. Williams, R. Risingsong, D. B. Royce, T. Honda, G. W. Gribble, M. B. Sporn, and J. J. Letterio (2006)
Clin. Cancer Res.
12, 4288-4293
|Abstract »|Full Text »|PDF »
Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways.
The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor.
I. S. Lucet, E. Fantino, M. Styles, R. Bamert, O. Patel, S. E. Broughton, M. Walter, C. J. Burns, H. Treutlein, A. F. Wilks, et al. (2006)
Blood
107, 176-183
|Abstract »|Full Text »|PDF »
Jak3 Kinase Domain Crystal Structures and Implications for Jak-Specific Drug Design..
T. J. Boggon (2005)
Blood (ASH Annual Meeting Abstracts)
106, 69
|Abstract »
Jak3 negatively regulates dendritic-cell cytokine production and survival.
K. Yamaoka, B. Min, Y.-J. Zhou, W. E. Paul, and J. J. O'Shea (2005)
Blood
106, 3227-3233
|Abstract »|Full Text »|PDF »
The Mannich Base NC1153 Promotes Long-Term Allograft Survival and Spares the Recipient from Multiple Toxicities.
S. M. Stepkowski, J. Kao, M.-E. Wang, N. Tejpal, H. Podder, L. Furian, J. Dimmock, A. Jha, U. Das, B. D. Kahan, et al. (2005)
J. Immunol.
175, 4236-4246
|Abstract »|Full Text »|PDF »
Identification of an Acquired Mutation in Jak2 Provides Molecular Insights into the Pathogenesis of Myeloproliferative Disorders.
M. Pesu, J. O'Shea, L. Hennighausen, and O. Silvennoinen (2005)
Mol. Interv.
5, 211-215
|Abstract »|Full Text »|PDF »
Structure of a Janus kinase: molecular insights and prospects for optimizing a new class of immunosuppressants.
J. J. O'Shea, M. Gadina, and X. Chen (2005)
Blood
106, 765-766
|Full Text »|PDF »
Crystal structure of the Jak3 kinase domain in complex with a staurosporine analog.
T. J. Boggon, Y. Li, P. W. Manley, and M. J. Eck (2005)
Blood
106, 996-1002
|Abstract »|Full Text »|PDF »
Viral Infection in the Renal Transplant Recipient.
M. Moriguchi, B. D. Hissong, M. Gadina, K. Yamaoka, H. L. Tiffany, P. M. Murphy, F. Candotti, and J. J. O'Shea (2005)
J. Biol. Chem.
280, 17408-17414
|Abstract »|Full Text »|PDF »
Immunosuppressive Drugs for Kidney Transplantation.
P. F. Halloran (2004)
N. Engl. J. Med.
351, 2715-2729
|Full Text »|PDF »
The JAK3 inhibitor CP-690550 selectively reduces NK and CD8+ cell numbers in cynomolgus monkey blood following chronic oral dosing.
M. Conklyn, C. Andresen, P. Changelian, and E. Kudlacz (2004)
J. Leukoc. Biol.
76, 1248-1255
|Abstract »|Full Text »|PDF »
Targeting the Jak/STAT pathway for immunosuppression.
J J O'Shea (2004)
Ann Rheum Dis
63, ii67-ii71
|Full Text »|PDF »
