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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenomatous Polyposis Coli Protein / genetics
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Adenomatous Polyposis Coli Protein / metabolism
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Administration, Oral
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Aged
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Animals
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Azoxymethane / toxicity
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Carcinogenesis / drug effects
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Carcinogenesis / genetics
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Carcinogenesis / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Transformation, Neoplastic / pathology
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Colorectal Neoplasms / chemically induced
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Colorectal Neoplasms / drug therapy*
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / pathology
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Crystallography, X-Ray
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Female
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Germinal Center Kinases
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Humans
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Imidazoles / pharmacology*
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Imidazoles / therapeutic use
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Nude
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Middle Aged
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Mutation
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Neoplastic Stem Cells / drug effects*
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Protein Binding
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Quinazolines / pharmacology*
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Quinazolines / therapeutic use
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Ubiquitin-Protein Ligases
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Wnt Proteins / metabolism
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Wnt Signaling Pathway / drug effects*
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Xenograft Model Antitumor Assays
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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Adenomatous Polyposis Coli Protein
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CTNNB1 protein, mouse
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Germinal Center Kinases
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Imidazoles
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Protein Kinase Inhibitors
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Quinazolines
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Recombinant Proteins
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Wnt Proteins
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adenomatous polyposis coli protein, mouse
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beta Catenin
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Ubiquitin-Protein Ligases
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Protein Serine-Threonine Kinases
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TNIK protein, human
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TNIK protein, mouse
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Azoxymethane