Small molecule–mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer

B Chen, ME Dodge, W Tang, J Lu, Z Ma… - Nature chemical …, 2009 - nature.com
B Chen, ME Dodge, W Tang, J Lu, Z Ma, CW Fan, S Wei, W Hao, J Kilgore, NS Williams
Nature chemical biology, 2009nature.com
The pervasive influence of secreted Wnt signaling proteins in tissue homeostasis and
tumorigenesis has galvanized efforts to identify small molecules that target Wnt-mediated
cellular responses. By screening a diverse synthetic chemical library, we have discovered
two new classes of small molecules that disrupt Wnt pathway responses; whereas one class
inhibits the activity of Porcupine, a membrane-bound acyltransferase that is essential to the
production of Wnt proteins, the other abrogates destruction of Axin proteins, which are …
Abstract
The pervasive influence of secreted Wnt signaling proteins in tissue homeostasis and tumorigenesis has galvanized efforts to identify small molecules that target Wnt-mediated cellular responses. By screening a diverse synthetic chemical library, we have discovered two new classes of small molecules that disrupt Wnt pathway responses; whereas one class inhibits the activity of Porcupine, a membrane-bound acyltransferase that is essential to the production of Wnt proteins, the other abrogates destruction of Axin proteins, which are suppressors of Wnt/β-catenin pathway activity. With these small molecules, we establish a chemical genetic approach for studying Wnt pathway responses and stem cell function in adult tissue. We achieve transient, reversible suppression of Wnt/β-catenin pathway response in vivo, and we establish a mechanism-based approach to target cancerous cell growth. The signal transduction mechanisms shown here to be chemically tractable additionally contribute to Wnt-independent signal transduction pathways and thus could be broadly exploited for chemical genetics and therapeutic goals.
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