1. C644-0303, a small-molecule inhibitor of the Wnt/β-catenin pathway, suppresses colorectal cancer growth.
- Author
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Yan Y, Zhang Y, Li M, Zhang Y, Zhang X, Zhang X, Xu Y, Wei W, Wang J, Xu X, Song Q, and Zhao C
- Subjects
- Adenomatous Polyposis Coli genetics, Adenomatous Polyposis Coli pathology, Animals, Apoptosis drug effects, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Cell Movement drug effects, Cell Survival drug effects, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Drug Discovery, Female, HCT116 Cells, HT29 Cells, Humans, Luciferases, MCF-7 Cells, Mice, Mice, Inbred BALB C, Mice, Nude, Molecular Targeted Therapy methods, Spheroids, Cellular drug effects, TCF Transcription Factors, Transcription Factors antagonists & inhibitors, Xenograft Model Antitumor Assays, beta Catenin genetics, Adenomatous Polyposis Coli drug therapy, Antineoplastic Agents therapeutic use, Colorectal Neoplasms drug therapy, Wnt Signaling Pathway drug effects
- 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., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Published
- 2021
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