Wnt信号通路
偶氮甲烷
结直肠癌
癌变
癌症研究
癌症干细胞
交通2
连环素
干细胞
生物
化学
癌症
细胞生物学
信号转导
免疫学
遗传学
肿瘤坏死因子α
肿瘤坏死因子受体
作者
Mari Masuda,Yuko Uno,Naomi Ohbayashi,Hirokazu Ohata,Ayako Mimata,Mutsuko Kukimoto‐Niino,Hideki Moriyama,Shigeki Kashimoto,Tomoko Inoue,Naoko Goto,Koji Okamoto,Mikako Shirouzu,Masaaki Sawa,Tesshi Yamada
摘要
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.
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