TY - JOUR
T1 - Tool inhibitors and assays to interrogate the biology of the TRAF2 and NCK interacting kinase
AU - Read, Jon
AU - Collie, Iain T.
AU - Nguyen-McCarty, Michelle
AU - Lucaj, Christopher
AU - Robinson, James
AU - Conway, Leslie
AU - Mukherjee, Jayanta
AU - McCall, Eileen
AU - Donohoe, Gerard
AU - Flavell, Elizabeth
AU - Peciak, Karolina
AU - Warwicker, Juli
AU - Dix, Carly
AU - Van den Hoven, Bernard G.
AU - Madin, Andrew
AU - Brown, Dean G.
AU - Moss, Stephen
AU - Haggarty, Stephen J.
AU - Brandon, Nicholas J.
AU - Bürli, Roland W.
N1 - Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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.
KW - Kinase selectivity
KW - Schizophrenia
KW - Tool inhibitors
KW - X-ray
UR - https://www.scopus.com/pages/publications/85066245046
U2 - 10.1016/j.bmcl.2019.05.032
DO - 10.1016/j.bmcl.2019.05.032
M3 - Article
SN - 0960-894X
VL - 29
SP - 1962
EP - 1967
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 15
ER -
