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

[Display omitted] 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 selec...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 29; no. 15; pp. 1962 - 1967
Main Authors:	Read, Jon, Collie, Iain T., Nguyen-McCarty, Michelle, Lucaj, Christopher, Robinson, James, Conway, Leslie, Mukherjee, Jayanta, McCall, Eileen, Donohoe, Gerard, Flavell, Elizabeth, Peciak, Karolina, Warwicker, Juli, Dix, Carly, Van den Hoven, Bernard G., Madin, Andrew, Brown, Dean G., Moss, Stephen, Haggarty, Stephen J., Brandon, Nicholas J., Bürli, Roland W.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-08-2019
Subjects:	Kinase selectivity Schizophrenia Tool inhibitors X-ray Tool inhibitors Schizophrenia X-ray Kinase selectivity
Online Access:	Get full text
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Summary:	[Display omitted] 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2019.05.032