title: TNIK inhibition abrogates colorectal cancer stemness.
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.
authors: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors: Mari
authors: M
authors: Masuda
authors: Carna Biosciences, Inc., BMA 3F 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors: Yuko
authors: Y
authors: Uno
authors: Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors: Naomi
authors: N
authors: Ohbayashi
authors: Division of Cancer Differentiation, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors: Hirokazu
authors: H
authors: Ohata
authors: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors: Ayako
authors: A
authors: Mimata
authors: Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors: Mutsuko
authors: M
authors: Kukimoto-Niino
authors: Carna Biosciences, Inc., BMA 3F 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors: Hideki
authors: H
authors: Moriyama
authors: Carna Biosciences, Inc., BMA 3F 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors: Shigeki
authors: S
authors: Kashimoto
authors: Carna Biosciences, Inc., BMA 3F 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors: Tomoko
authors: T
authors: Inoue
authors: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors: Naoko
authors: N
authors: Goto
authors: Division of Cancer Differentiation, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors: Koji
authors: K
authors: Okamoto
authors: Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors: Mikako
authors: M
authors: Shirouzu
authors: Carna Biosciences, Inc., BMA 3F 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors: Masaaki
authors: 0000-0002-0077-2188
authors: M
authors: Sawa
authors: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors: Tesshi
authors: T
authors: Yamada
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000284:Administration, Oral; D000368:Aged; D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018360:Crystallography, X-Ray; D005260:Female; D000081410:Germinal Center Kinases; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D008875:Middle Aged; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C495267:CTNNB1 protein, mouse; D000081410:Germinal Center Kinases; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011994:Recombinant Proteins; D051153:Wnt Proteins; C000613192:adenomatous polyposis coli protein, mouse; D051176:beta Catenin; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; C000631454:TNIK protein, human; C545105:TNIK protein, mouse; D001397:Azoxymethane