© 2016 Elsevier Ireland Ltd Activation of Wnt/β-catenin signaling is associated with pancreatic and colorectal cancer, among others. To-date, there are no FDA-approved small molecule Wnt/β-catenin inhibitors and many past efforts resulted in compounds with undesirable off-target effects. We recently identified a series of benzimidazole analogs as potent inhibitors of Wnt/β-catenin signaling. Here, we show that the lead compound SRI36160 displayed selective Wnt inhibition and potent antiproliferative activity in pancreatic and colorectal cancer cells. Moreover, SRI36160 had no effect on STAT3 and mTORC1 signaling in pancreatic and colorectal cancer cells, and was not effective in inhibiting proliferation of non-cancerous cells. Our findings suggest that this series of benzimidazole analogs presents a novel approach for the treatment of Wnt-dependent cancers such as colorectal and pancreatic cancer.