Tyrosine Kinase 2-Mediated Signal Transduction in T Lymphocytes Is Blocked by Pharmacological Stabilization of its Pseudokinase Domain (original) (raw)

The Journal of biological chemistry, 2015

Abstract

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 ligande...

Jeffrey Tredup hasn't uploaded this paper.

Let Jeffrey know you want this paper to be uploaded.

Ask for this paper to be uploaded.