Open AccessC644‐0303, a small‐molecule inhibitor of the Wnt/β‐catenin pathway, suppresses colorectal cancer growth
Author(s) -
Yan Yu,
Zhang Yidan,
Li Mengyuan,
Zhang Yazhuo,
Zhang Xinxin,
Zhang Xiaonan,
Xu Yuting,
Wei Wei,
Wang Jie,
Xu Xiaohan,
Song Qiaoling,
Zhao Chenyang
Publication year - 2021
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.15118
Subject(s) - wnt signaling pathway , adenomatous polyposis coli , cancer research , colorectal cancer , catenin , transcription factor , cell growth , cancer , cell cycle , beta catenin , signal transduction , chemistry , microbiology and biotechnology , biology , medicine , gene , biochemistry
Abstract The Wnt/β‐catenin signaling pathway plays an important role in tissue homeostasis, and its malignant activation is closely related to the occurrence and development of many cancers, especially colorectal cancer with adenomatous polyposis coli (APC) and CTNNB1 mutations. By applying a TCF/lymphoid‐enhancing factor (LEF) luciferase reporter system, the high‐throughput screening of 18 840 small‐molecule compounds was performed. A novel scaffold compound, C644‐0303, was identified as a Wnt/β‐catenin signaling inhibitor and exhibited antitumor efficacy. It inhibited both constitutive and ligand activated Wnt signals and its downstream gene expression. Functional studies showed that C644‐0303 causes cell cycle arrest, induces apoptosis, and inhibits cancer cell migration. Moreover, transcription factor array indicated that C644‐0303 could suppress various tumor‐promoting transcription factor activities in addition to Wnt/β‐catenin. Finally, C644‐0303 suppressed tumor spheroidization in a 3‐dimensional cell culture model and inhibited xenograft tumor growth in mice. In conclusion, we report a novel structural small molecular inhibitor targeting the Wnt/β‐catenin signaling pathway that has therapeutic potential for colorectal cancer treatment.