icg-001 and Adenomatous-Polyposis-Coli

Inherited and somatic mutations in the adenomatous polyposis coli occur in most colon cancers, leading to activation of beta-catenin-responsive genes. To identify small molecule antagonists of this pathway, we challenged transformed colorectal cells with a secondary structure-templated chemical library, looking for compounds that inhibit a beta-catenin-responsive reporter. We identified ICG-001, a small molecule that down-regulates beta-catenin/T cell factor signaling by specifically binding to cyclic AMP response element-binding protein. ICG-001 selectively induces apoptosis in transformed cells but not in normal colon cells, reduces in vitro growth of colon carcinoma cells, and is efficacious in the Min mouse and nude mouse xenograft models of colon cancer.

Topics: Adenomatous Polyposis Coli; Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Cell Line; Colon; Colonic Neoplasms; Cyclic AMP Response Element-Binding Protein; Cyclin D1; Cytoskeletal Proteins; DNA-Binding Proteins; Epithelial Cells; Gene Expression Regulation; Inhibitor of Apoptosis Proteins; Lymphoid Enhancer-Binding Factor 1; Male; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Molecular Structure; Neoplasm Proteins; Pyrimidinones; Signal Transduction; Survivin; Trans-Activators; Transcription Factors; Transcription, Genetic