Mutations in the gene encoding the Adenomatous Polyposis Coli (APC) protein are a highly frequent and early event in colorectal cancers (CRC). Over 90 percent of mutations in the APC gene generate stable truncated gene products, leading to activation of the Wnt signaling pathway and deregulation of multiple cellular processes. However, there have been no therapeutic approaches directly targeting these APC mutations. We have performed a chemical screen employing a series of isogenic normal and partially transformed immortalized human colonic epithelial cells (HCECs) to identify small molecules that are selectively toxic to CRC lines with APC truncations while sparing cells with wild type (WT) APC. The lead compounds and their analogs exhibit antitumor activity in both xenograft and genetically engineered colorectal cancer mouse models. Current work is focusing on the investigation of the mechanism of action of these compounds and optimization of the lead compounds for future translational development as drugs for clinical testing.