2. Academic Validation
  3. Tool inhibitors and assays to interrogate the biology of the TRAF2 and NCK interacting kinase

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

  • Bioorg Med Chem Lett. 2019 Aug 1;29(15):1962-1967. doi: 10.1016/j.bmcl.2019.05.032.
Jon Read 1,  Iain T Collie 1,  Michelle Nguyen-McCarty 2,  Christopher Lucaj 3,  James Robinson 1,  Leslie Conway 3,  Jayanta Mukherjee 3,  Eileen McCall 1,  Gerard Donohoe 1,  Elizabeth Flavell 4,  Karolina Peciak 4,  Juli Warwicker 4,  Carly Dix 1,  Bernard G Van den Hoven 5,  Andrew Madin 1,  Dean G Brown 6,  Stephen Moss 3,  Stephen J Haggarty 2,  Nicholas J Brandon 7,  Roland W Bürli 8
Affiliations

Affiliations

  • 1 Discovery Sciences, IMED Biotech Unit, AstraZeneca, Cambridge CB4 0WG, UK.
  • 2 Departments of Neurology and Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 3 AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Boston, MA 02111, USA.
  • 4 Discovery Sciences, IMED Biotech Unit, AstraZeneca, Alderley Park, SK10 4TG, UK.
  • 5 TC Scientific Inc., 4298 91A Street NW, Edmonton, AB T6E 5V2, Canada.
  • 6 Discovery Sciences, IMED Biotech Unit, AstraZeneca Boston, Waltham, MA 02451, USA.
  • 7 Neuroscience, IMED Biotech Unit, AstraZeneca Boston, Waltham, MA 02451, USA. Electronic address: [email protected].
  • 8 Neuroscience, IMED Biotech Unit, AstraZeneca, Cambridge CB21 6GH, UK. Electronic address: [email protected].
PMID: 31153805 DOI: 10.1016/j.bmcl.2019.05.032
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.

Keywords

Kinase selectivity; Schizophrenia; Tool inhibitors; X-ray.

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