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Issue 4, 2017
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Identification of imidazo[1,2-b]pyridazine TYK2 pseudokinase ligands as potent and selective allosteric inhibitors of TYK2 signalling

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Abstract

As a member of the Janus (JAK) family of non-receptor tyrosine kinases, TYK2 mediates the signaling of pro-inflammatory cytokines including IL-12, IL-23 and type 1 interferon (IFN), and therefore represents an attractive potential target for treating the various immuno-inflammatory diseases in which these cytokines have been shown to play a role. Following up on our previous report that ligands to the pseudokinase domain (JH2) of TYK2 suppress cytokine-mediated receptor activation of the catalytic (JH1) domain, the imidazo[1,2-b]pyridazine (IZP) 7 was identified as a promising hit compound. Through iterative modification of each of the substituents of the IZP scaffold, the cellular potency was improved while maintaining selectivity over the JH1 domain. These studies led to the discovery of the JH2-selective TYK2 inhibitor 29, which provided encouraging systemic exposures after oral dosing in mice. Phosphodiesterase 4 (PDE4) was identified as an off-target and potential liability of the IZP ligands, and selectivity for TYK2 JH2 over this enzyme was obtained by elaborating along selectivity vectors determined from analyses of X-ray co-crystal structures of representative ligands of the IZP class bound to both proteins.

Graphical abstract: Identification of imidazo[1,2-b]pyridazine TYK2 pseudokinase ligands as potent and selective allosteric inhibitors of TYK2 signalling

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Supplementary files

Article information


Submitted
10 Oct 2016
Accepted
06 Dec 2016
First published
15 Dec 2016

Med. Chem. Commun., 2017,8, 700-712
Article type
Research Article

Identification of imidazo[1,2-b]pyridazine TYK2 pseudokinase ligands as potent and selective allosteric inhibitors of TYK2 signalling

R. Moslin, D. Gardner, J. Santella, Y. Zhang, J. V. Duncia, C. Liu, J. Lin, J. S. Tokarski, J. Strnad, D. Pedicord, J. Chen, Y. Blat, A. Zupa-Fernandez, L. Cheng, H. Sun, C. Chaudhry, C. Huang, C. D'Arienzo, J. S. Sack, J. K. Muckelbauer, C. Chang, J. Tredup, D. Xie, N. Aranibar, J. R. Burke, P. H. Carter and D. S. Weinstein, Med. Chem. Commun., 2017, 8, 700
DOI: 10.1039/C6MD00560H

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