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

  • Science. 2003 Oct 31;302(5646):875-8. doi: 10.1126/science.1087061.
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
Affiliations
  • 1. Immunology Group, Department of Antibacterials and Immunology, Pfizer Global Researchand Development, Groton, CT 06340, USA. [email protected]
PMID: 14593182 DOI: 10.1126/science.1087061
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.