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. 2003 Oct 31;302(5646):875-8.
doi: 10.1126/science.1087061.

Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor

Paul S Changelian  1 , Mark E Flanagan, Douglas J Ball, Craig R Kent, Kelly S Magnuson, William H Martin, Bonnie J Rizzuti, Perry S Sawyer, Bret D Perry, William H Brissette, Sandra P McCurdy, Elizabeth M Kudlacz, Maryrose J Conklyn, Eileen A Elliott, Erika R Koslov, Michael B Fisher, Timothy J Strelevitz, Kwansik Yoon, David A Whipple, Jianmin Sun, Michael J Munchhof, John L Doty, Jeffrey M Casavant, Todd A Blumenkopf, Michael Hines, Matthew F Brown, Brett M Lillie, Chakrapani Subramanyam, Chang Shang-Poa, Anthony J Milici, Gretchen E Beckius, James D Moyer, Chunyan Su, Thasia G Woodworth, Anderson S Gaweco, Chan R Beals, Bruce H Littman, Douglas A Fisher, James F Smith, Panayiotis Zagouras, Holly A Magna, Mary J Saltarelli, Kimberly S Johnson, Linda F Nelms, Shelley G Des Etages, Lisa S Hayes, Thomas T Kawabata, Deborah Finco-Kent, Deanna L Baker, Michael Larson, Ming-Sing Si, Ricardo Paniagua, John Higgins, Bari Holm, Bruce Reitz, Yong-Jie Zhou, Randall E Morris, John J O'Shea, Dominic C Borie
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Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor

Paul S Changelian et al. Science. .

Abstract

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 inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.

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