Article abstract


Nature Chemical Biology 5, 100 - 107 (2009)
Published online: 4 January 2009 | doi:10.1038/nchembio.137

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

Baozhi Chen1,4, Michael E Dodge1,4, Wei Tang1, Jianming Lu2, Zhiqiang Ma2, Chih-Wei Fan1, Shuguang Wei2, Wayne Hao2, Jessica Kilgore2, Noelle S Williams2, Michael G Roth2, James F Amatruda3, Chuo Chen2 & Lawrence Lum1


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.

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  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 Lum1 e-mail: lawrence.lum@utsouthwestern.edu



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