Tool inhibitors and assays to interrogate the biology of the TRAF2 and NCK interacting kinase. Issue 15 (1st August 2019)

• Record Type: Journal Article
• 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.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 15(2019)
• Page Start: 1962
• Page End: 1967
• Publication Date: 2019-08-01
• Subjects: Tool inhibitors -- Kinase selectivity -- X-ray -- Schizophrenia; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.05.032
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.