Tyrosine Kinase 2-Mediated Signal Transduction in T Lymphocytes Is Blocked by Pharmacological Stabilization of its Pseudokinase Domain [Protein Structure and Folding]

March 11th, 2015 by Tokarski, J. S., Zupa-Fernandez, A., Tredup, J. A., Pike, K., Chang, C., Xie, D., Cheng, L., Pedicord, D., Muckelbauer, J., Johnson, S. R., Wu, S., Edavettal, S. C., Hong, Y., Witmer, M. R., Elkin, L. L., Blat, Y., Pitts, W. J., Weinstein, D. S., Bur

Inhibition of signal transduction downstream of the IL-23 receptor represents an intriguing approach to the treatment of autoimmunity. Using a chemogenomics approach marrying kinome-wide inhibitory profiles of a compound library with the cellular activity against an IL-23-stimulated transcriptional response in T lymphocytes, a class of inhibitors was identified which bind to and stabilize the pseudokinase domain of the Janus kinase tyrosine kinase 2 (Tyk2), resulting in blockade of receptor-mediated activation of the adjacent catalytic domain. These Tyk2 pseudokinase domain stabilizers were also shown to inhibit Tyk2-dependent signaling through the Type I interferon receptor (IFNAR), but not Tyk2-independent signaling and transcriptional cellular assays including stimulation through the receptors for IL-2 (JAK1 and JAK3 dependent) and thrombopoietin (JAK2 dependent) demonstrating the high functional selectivity of this approach. A crystal structure of the pseudokinase domain liganded with a representative example showed the compound bound to a site analogous to the ATP-binding site in catalytic kinases with features consistent with high ligand selectivity. The results support a model where the pseudokinase domain regulates activation of the catalytic domain by forming receptor-regulated inhibitory interactions. Tyk2 pseudokinase stabilizers, therefore, represent a novel approach to the design of potent and selective agents for the treatment of autoimmunity.
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