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Publication Abstract from PubMed

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.

Tyrosine Kinase 2-Mediated Signal Transduction in T Lymphocytes Is Blocked by Pharmacological Stabilization of its Pseudokinase Domain.,Tokarski JS, Zupa-Fernandez A, Tredup JA, Pike K, Chang C, Xie D, Cheng L, Pedicord D, Muckelbauer J, Johnson SR, Wu S, Edavettal SC, Hong Y, Witmer MR, Elkin LL, Blat Y, Pitts WJ, Weinstein DS, Burke JR J Biol Chem. 2015 Mar 11. pii: jbc.M114.619502. PMID:25762719^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.