Tool inhibitors and assays to interrogate the biology of the TRAF2 and NCK interacting kinase.

Abstract

The TRAF2 and NCK interacting kinase (TNIK) has been proposed to play a role in cytoskeletal organization and synaptic plasticity and has been linked, among others, to neurological disorders. However, target validation efforts for TNIK have been hampered by the limited kinase selectivity of small molecule probes and possible functional compensation in mouse models. Both issues are at least in part due to its close homology to the kinases MINK1 (or MAP4K6) and MAP4K4 (or HGK). As part of our interest in validating TNIK as a therapeutic target for neurological diseases, we set up a panel of biochemical and cellular assays, which are described herein. We then examined the activity of known amino-pyridine-based TNIK inhibitors (1, 3) and prepared structurally very close analogs that lack the ability to inhibit the target. We also developed a structurally orthogonal, naphthyridine-based TNIK inhibitor (9) and an inactive control molecule of the same chemical series. These validated small-molecule probes will enable dissection of the function of TNIK family in the context of human disease biology.

• Authors: Jon Read, Iain T Collie, Michelle Nguyen-McCarty, Christopher Lucaj, James Robinson, Leslie Conway, Jayanta Mukherjee, Eileen McCall, Gerard Donohoe, Elizabeth Flavell, Karolina Peciak, Juli Warwicker, Carly Dix, Bernard G Van den Hoven, Andrew Madin, Dean G Brown, Stephen Moss, Stephen J Haggarty, Nicholas J Brandon, Roland W Bürli
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 29 Issue 15 Pg. 1962-1967 (08 01 2019) ISSN: 1464-3405 [Electronic] England
• PMID: 31153805 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• TNF Receptor-Associated Factor 2
• Protein Serine-Threonine Kinases
• TNIK protein, human

Topics

• Biological Assay
• Humans
• Molecular Structure
• Protein Serine-Threonine Kinases (metabolism)
• Schizophrenia (genetics)
• TNF Receptor-Associated Factor 2 (metabolism)