Small Molecule-Mediated Disruption of Wnt-dependent Signaling in Tissue Regeneration and Cancer

Nat Chem Biol. 2009 Feb;5(2):100-7. doi: 10.1038/nchembio.137. Epub 2009 Jan 4.

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/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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Axin Protein
  • Humans
  • Molecular Structure
  • Neoplasms / metabolism*
  • Regeneration*
  • Repressor Proteins / metabolism
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • Wnt Proteins / metabolism
  • Wnt Proteins / physiology*
  • beta Catenin / metabolism
  • beta Catenin / physiology

Substances

  • Axin Protein
  • Repressor Proteins
  • Wnt Proteins
  • beta Catenin

Associated data

  • PubChem-Substance/56413306
  • PubChem-Substance/56413307
  • PubChem-Substance/56413308
  • PubChem-Substance/56413309
  • PubChem-Substance/56413310
  • PubChem-Substance/56413311
  • PubChem-Substance/56413312
  • PubChem-Substance/56413313
  • PubChem-Substance/56413314
  • PubChem-Substance/56413315
  • PubChem-Substance/56413316
  • PubChem-Substance/56413317
  • PubChem-Substance/56413318