The Wnt family of signaling proteins influences most aspects of metazoan embryonic development and post-embryonic tissue homeostasis1
. Cellular responses to these proteins are often categorized based on their utilization of β-catenin, a co-activator of the TCF/LEF family of transcriptional effectors. Similar to other signal transduction pathways required for cell fate decision-making, activity of the Wnt/β-catenin (“canonical”) pathway maintains transcriptional programs that enable stem cells to remain multi-potent2,3
. Inability to sustain these transcription programs results in compromised ability of stem cells to self-renew2,4-6
Pathological states that may arise from altered stem cell function, such as degenerative diseases and cancer, are frequently associated with changes in Wnt/β-catenin pathway activity. Indeed, hyperactivation of the Wnt/β-catenin pathway is thought to induce premature senescence of stem cells and age-related loss of stem cell function7,8
. In cancer, hyperactivation of the Wnt/β-catenin pathway, often in conjunction with mutations in other cell growth regulatory genes, can lead to aberrant cell growth9
. Notably, 90% of colorectal cancers harbor loss-of-function mutations in the adenomatosis polyposis coli
) gene, a major suppressor of the Wnt/β-catenin pathway10,11
. Less frequently, loss of extracellular inhibitors that normally suppress Wnt protein function may give rise to Wnt ligand-dependent tumors12
Much of our understanding of Wnt/β-catenin pathway response in adult animal tissues has been limited by the inability to deploy classical genetic approaches without additionally impacting normal embryonic development. Thus, despite a general agreement that targeting the Wnt signal transduction pathway would be potentially useful in a broad range of diseases, the consequences of inhibiting Wnt function in adult tissue homeostasis are unknown. Identification of small molecule inhibitors of the Wnt/β-catenin pathway would enable a chemical genetics-based interrogation of pathway function that bypasses the limitations of typical genetic approaches, and facilitate development of therapeutically useful reagents. So far, efforts to achieve chemical control of the Wnt/β-catenin pathway have been hindered by a lack of knowledge regarding underlying signal transduction mechanisms that are amenable to chemical manipulation. This deficiency is underscored by the fact that there are currently no chemicals targeting this pathway in clinical testing.
In order to identify lead chemical structures that will facilitate the study of Wnt/β-catenin responses in adult tissue homeostasis and disease, we screened a diverse synthetic chemical library and identified two general classes of compounds that target discrete regulatory steps within the pathway. Using these chemicals, we demonstrate the ability to transiently and reversibly suppress regenerative processes in adult tissue and to abolish aberrant Wnt/β-catenin responses in cancerous cells in vitro. Our findings should facilitate the use of chemical genetic approaches to study Wnt protein function in adult animals and the development of therapeutic approaches premised upon attack of Wnt-mediated cellular responses.