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Aberrant activation of the Wnt/β‐catenin signaling pathway has been observed in a wide range of human tumors. Deregulation of the pathway is closely linked to various aspects of human carcinogenesis such as cell viability, regulation of cell cycle, epithelial‐mesenchymal transition, and maintenance of stemness. In addition, recent studies have disclosed the involvement of Wnt signaling in immune evasion of tumor cells. The accumulation of β‐catenin in the nucleus is a common feature of cancer cells carrying defects in the pathway, which leads to the continuous activation of T‐cell factor (TCF)/LEF transcription factors. Consequently, a genetic program is switched on, leading to the uncontrolled growth, prolonged survival, and acquisition of mesenchymal phenotype. As β‐catenin/TCF serves as a signaling hub for the pathway, β‐catenin/TCF‐dependent transcriptional activity is a relevant readout of the pathway. To date, a wide variety of synthetic TCF/LEF reporters has been developed, and high‐throughput screening (HTS) using these reporters has made significant contributions to the discovery of Wnt inhibitors. Indeed, HTS led to the identification of chemical probes targeting porcupine, a membrane bound O‐acyltransferase, and CREB‐binding protein, a transcriptional coactivator. This review focuses on various screening strategies for the discovery of Wnt inhibitors and their mode of action to help the creation of new concepts for assay/screening methods.

Discovery of chemical probes that suppress Wnt/β‐catenin signaling through high‐throughput screening