Inherited and somatic mutations in the APC gene, a human tumor-suppressor, occur in a large percentage of colon cancers, leading to elevated levels of nuclear β-Catenin, and to activation of TCF/ β-Catenin-responsive genes including cyclin D1 and c-myc. To identify small molecule antagonists of this pathway, we screened transformed colorectal cells with a secondary structure-templated chemical library, in search of compounds that attenuated a TCF/ β- Catenin-responsive reporter gene. From this library we selected ICG-001 (IC50 = 3 M) as a lead compound. Design and synthesis of the chemical library and some preliminary biological evaluation is described.