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

Baozhi Chen, Michael E. Dodge, Wei Tang, Jianming Lu, Zhiqiang Ma, Chih Wei Fan, Shuguang Wei, Wayne Hao, Jessica Kilgore, Noelle S. Williams, Michael G. Roth, James F. Amatruda, Chuo Chen, Lawrence Lum

Research output: Contribution to journalArticlepeer-review

940 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)100-107
Number of pages8
JournalNature chemical biology
Volume5
Issue number2
DOIs
StatePublished - Feb 6 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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