Colorectal cancer (CRC) is the third most common cause of cancer death in the USA. Germline mutations in the apc tumor suppressor gene, one of the key players in the development of CRC and an important component in the Wnt/beta-catenin signaling pathway, are responsible for familial adenomatous polyposis (FAP). Mutations that result in constitutive activation of the Wnt/ß-catenin signaling pathway can lead to colon cancer. Wnt(s) have diverse roles in regulating cell fate, proliferation, migration, and death. beta-Catenin is highly expressed in many cancer cell types and promotes growth and tumor formation. Elevated beta-catenin activity in carcinogenesis model systems and neoplastic tissues suggests that this enzyme is a valid target for chemoprevention. By using computational biology with BlueGene/L and GPU supercomputers, we have identified/synthesized several small molecule inhibitors of beta-catenin that are highly effective or have good potential to suppress colon carcinogenesis. In this application, we propose to use state of the art technologies to continue to identify, characterize, test and validate novel, nontoxic small molecule inhibitors of beta-catenin. Our approaches include determination of binding, binding affinities, identification of the specific binding sites, and examining the resulting structural changes by computational simulation using our supercomputer systems. We will validate the effectiveness of these inhibitors by performing protein binding assays, cell transformation assays and in vivo animal experiments, including xenograft models and the AOM-induced colon cancer and APCMin mouse models. Through these studies, we will develop more effective agents targeting beta-catenin with fewer side effects for the chemoprevention of colon cancer.