The specificity of JAK3 kinase inhibitors

• Published in: Blood Vol. 111; no. 4; pp. 2155 - 2157
• Main Authors: Changelian, Paul S., Moshinsky, Deborah, Kuhn, Cyrille F., Flanagan, Mark E., Munchhof, Michael J., Harris, Thomas M., Whipple, David A., Doty, Jonathan L., Sun, Jianmin, Kent, Craig R., Magnuson, Kelly S., Perregaux, David G., Sawyer, Perry S., Kudlacz, Elizabeth M.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.02.2008; The Americain Society of Hematology
• Subjects: Arthritis, Rheumatoid - drug therapy; Biological and medical sciences; Clinical Trials as Topic; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Graft Rejection - prevention & control; Humans; Immunomodulators; Janus Kinase 3 - antagonists & inhibitors; Kinetics; Medical sciences; Pharmacology. Drug treatments; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Pyrroles - pharmacology; Pyrroles - therapeutic use; Quinazolines - pharmacology; Quinazolines - therapeutic use; Enzyme; Transferases; Rodentia; Epidermal growth factor receptor; Immunomodulator; In vivo; Vertebrata; Specificity; Mammalia; Mouse; Analog; Animal; Inhibitor; Immunosuppressive agent; Protein-tyrosine kinase
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-09-115030

PF-956980 is a selective inhibitor of JAK3, related in structure to CP-690550, a compound being evaluated in clinical trials for rheumatoid arthritis and prevention of allograft rejection. PF-956980 has been evaluated against a panel of 30 kinases, and found to have nanomolar potency against only JAK3. Cellular and whole blood activity of this compound parallels its potency and selectivity in enzyme assays. It was effective in vivo at inhibiting the delayed type hypersensivity reaction in mice. We compared 2 commercially available JAK3 inhibitors (WHI-P131 and WHI-P154) in the same panel of biochemical and cellular assays and found them to be neither potent nor selective for JAK3. Both were found to be nanomolar inhibitors of the EGF receptor family of kinases. As these compounds have been used in numerous publications in the transplant and autoimmune disease literature, their specificity should be considered when interpreting these results.