Baozhi Chen ^{1, 4}, Michael E Dodge ^{1, 4}, Wei Tang ¹, Jianming Lu ², Zhiqiang Ma ², Chih-Wei Fan ¹, Shuguang Wei ², Wayne Hao ², Jessica Kilgore ², Noelle S Williams ², Michael G Roth ², James F Amatruda ³, Chuo Chen ² and Lawrence Lum ¹

¹ Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
² Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
³ Departments of Pediatrics, Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
⁴ These authors contributed equally to this work.

Correspondence to: Lawrence Lum ¹     e-mail: lawrence.lum@utsouthwestern.edu

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/beta-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/beta-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.

http://www.nature.com/nchembio/journal/v5/n2/suppinfo/nchembio.137_S1.html
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Suppl. Figure 1: Identification of small molecule antagonists of the Wnt/b-catenin signal transduction pathway.

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