Tyrosine Kinase 2-mediated Signal Transduction in T Lymphocytes Is Blocked by Pharmacological Stabilization of Its Pseudokinase Domain.

Autor:	Tokarski JS; From the Departments of Molecular Structure and Design., Zupa-Fernandez A; Immunosciences Biology., Tredup JA; Protein Science., Pike K; the Department of Leads Discovery and Optimization, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut 06492., Chang C; From the Departments of Molecular Structure and Design., Xie D; Protein Science., Cheng L; Immunosciences Biology., Pedicord D; Leads Discovery and Optimization, and., Muckelbauer J; From the Departments of Molecular Structure and Design., Johnson SR; From the Departments of Molecular Structure and Design., Wu S; Protein Science., Edavettal SC; Protein Science., Hong Y; Discovery Chemistry, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543 and., Witmer MR; Protein Science., Elkin LL; the Department of Leads Discovery and Optimization, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut 06492., Blat Y; Leads Discovery and Optimization, and., Pitts WJ; Discovery Chemistry, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543 and., Weinstein DS; Discovery Chemistry, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543 and., Burke JR; Immunosciences Biology, james.burke@bms.com.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2015 Apr 24; Vol. 290 (17), pp. 11061-74. Date of Electronic Publication: 2015 Mar 11.
DOI:	10.1074/jbc.M114.619502
Abstrakt:	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 that 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 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. (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)
Databáze:	MEDLINE
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