5D7A

Crystal structure of the kinase domain of TRAF2 and NCK-interacting protein kinase with NCB-0846

Summary for 5D7A

• Entry DOI: 10.2210/pdb5d7a/pdb
• Related: 5AX9 5CWZ
• Descriptor: TRAF2 and NCK-interacting protein kinase, cis-4-{[2-(1H-benzimidazol-5-ylamino)quinazolin-8-yl]oxy}cyclohexanol, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 106643.44

Authors

Ohbayashi, N.,Kukimoto-Niino, M.,Yamada, T.,Shirouzu, M. (deposition date: 2015-08-13, release date: 2016-08-17, Last modification date: 2023-11-08)

Primary citation

Masuda, M.,Uno, Y.,Ohbayashi, N.,Ohata, H.,Mimata, A.,Kukimoto-Niino, M.,Moriyama, H.,Kashimoto, S.,Inoue, T.,Goto, N.,Okamoto, K.,Shirouzu, M.,Sawa, M.,Yamada, T.
TNIK inhibition abrogates colorectal cancer stemness
Nat Commun, 7:12586-12586, 2016

PubMed Abstract: Canonical Wnt/β-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and β-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik(-/-)/Apc(min/+) mutant mice develop significantly fewer intestinal tumours. Here we report the first orally available small-molecule TNIK inhibitor, NCB-0846, having anti-Wnt activity. X-ray co-crystal structure analysis reveals that NCB-0846 binds to TNIK in an inactive conformation, and this binding mode seems to be essential for Wnt inhibition. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apc(min/+) mice and the sphere- and tumour-forming activities of colorectal cancer cells. TNIK is required for the tumour-initiating function of colorectal cancer stem cells. Its inhibition is a promising therapeutic approach.

PubMed: 27562646
DOI: 10.1038/ncomms12586

Experimental method

X-RAY DIFFRACTION (2.9 Å)