We describe the rational generation of small-molecule agents that suppress tumor cell growth by down-regulating canonical Wnt signaling. We first produced a chemical library of the derivatives of indole-2-ketones and carbinols; we then screened them by using scalable assays of biochemical antagonism of Dishevelled-1 PDZ domain interactions and cell-based assays of Dishevelled-1-driven T-cell factor-mediated transcription. Compounds showing parallel effects in these assays were tested for selective induction of apoptosis in cancer cells. A new compound (24) that met the criteria for high biochemical antagonism, T-cell factor-mediated transcription, and induction of tumor-selective apoptosis was found to significantly suppress the growth of tumor xenografts in mice.