C644-0303, a small-molecule inhibitor of the Wnt/β-catenin pathway, suppresses colorectal cancer growth

The Wnt/beta-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/beta-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/beta-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/beta-catenin signaling pathway that has therapeutic potential for colorectal cancer treatment.

Automated summary

The Wnt/beta-catenin signaling pathway is crucial in tissue homeostasis and its malignant activation is linked to various cancers, particularly colorectal cancer. Through high-throughput screening, a new inhibitor named C644-0303 was discovered to inhibit Wnt signaling and show antitumor efficacy by inducing cell cycle arrest, apoptosis, and inhibiting cancer cell migration. Further studies indicated its potential therapeutic benefits for colorectal cancer treatment.