Aberrant activation of Wnt/β-catenin signaling is a necessary initiating event in the genesis of most colorectal cancers. Loss-of-function mutations in the tumor suppressor gene adenomatous polyposis coli (APC) are present in about 80% of all colorectal cancers, and gain-of-function mutations in the oncogene CTNNB1 (β-catenin encoding gene) exist in approximately 10% of colorectal cancers. Both APC and CTNNB1 mutations lead to cytosolic accumulation and nuclear translocation of β-catenin, and therefore constitutive activation of β-catenin/TCF4-mediated gene transcription. As such, the Wnt/β-catenin pathway has emerged as one of the most promising targets for colorectal cancer treatment. Despite tremendous efforts in the past decade, there are no small molecule Wnt inhibitors approved by the FDA for cancer treatment. Recent work in our laboratories has identified a series of benzimidazoles as potent Wnt/β-catenin inhibitors. Here, we show that several benzimidazoles displayed strong activities against Wnt/β-catenin signaling in colorectal cancer cells harboring mutations in CTNNB1 or APC. In particular, SRI36324, the lead compound in this series, inhibited Wnt/β-catenin signaling in colorectal cancer HCT116 and DLD-1 cells with IC50 values of 4.1 and 3.7 nM, respectively. Moreover, the benzimidazole compounds exhibited potent activities against colorectal cancer cell proliferation under both standard cell culture conditions (adherent cells in complete medium containing 10% FBS) and conditions designed to enrich for cancer initiating cells. In addition, the benzimidazole compounds had no off-target effects on other pathways (e.g., STAT3 and mTORC1 signaling) in colorectal cancer cells, and were less antiproliferative to non-cancerous cells. Together, our findings indicate that the benzimidazole compounds are promising candidates for development as novel therapeutic agents for colorectal cancer.

Note: This abstract was not presented at the meeting.

Citation Format: Yonghe Li, Patsy G. Oliver, Wenyan Lu, Vibha Pathak, Corinne E. Augelli-Szafran, Donald J. Buchsbaum, Mark J. Suto. Discovery of a series of benzimidazoles as potent Wnt/β-catenin signaling inhibitors in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5173. doi:10.1158/1538-7445.AM2017-5173