Inherited and somatic mutations in the adenomatous polyposis coli occur in most colon cancers, leading to activation of β-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 β-catenin-responsive reporter. We identified ICG-001, a small molecule that down-regulates β-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.

Embryonic stem cells (ESCs) represent an important research tool and a potential resource for regenerative medicine. Generally, ESCs are cocultured with a supportive feeder cell layer of murine embryonic fibroblasts, which maintain the ESCs' capacity for selfrenewal and block spontaneous differentiation. These cumbersome conditions, as well as the risk of xenobiotic contamination of human ESCs grown on murine embryonic fibroblasts, make it a priority to develop chemically defined methods that can be safely used for the expansion of ESCs. Using a high-throughput, cellbased assay, we identified the small molecule IQ-1 that allows for the Wnt/␤-catenin-driven long-term expansion of mouse ESCs and prevents spontaneous differentiation. We demonstrate that IQ-1, by targeting the PR72/130 subunit of the serine/threonine phosphatase PP2A, prevents ␤-catenin from switching coactivator usage from CBP to p300. The increase in ␤-catenin/CBP-mediated transcription at the expense of ␤-catenin/p300-mediated transcription is critical for the maintenance of murine stem cell pluripotency. p300 ͉ PP2A ͉ Wnt signaling ͉ Nkd ͉ small molecule

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