Small-molecule synergist of the Wnt/β-catenin signaling pathway

Qisheng Zhang, Michael B. Major, Shinichi Takanashi, Nathan D. Camp, Naoyuki Nishiya, Eric C. Peters, Mark H. Ginsberg, Peter G. Schultz, Randall T. Moon, Sheng Ding

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

The Wnt/β-catenin signaling pathway regulates cell fate and behavior during embryogenesis, adult tissue homeostasis, and regeneration. When inappropriately activated, the pathway has been linked to colorectal cancer and melanoma, and when attenuated it may contribute to Alzheimer's disease and osteoporosis. Small molecules that modulate Wnt signaling will likely provide new insights into the regulation of this key developmental pathway and ultimately provide pharmacological agents to control Wnt signaling in vivo. To this end, we screened a library of 100,000 small molecules for activity in a cell-based assay of Wnt/β-catenin signaling and discovered a purine derivative, QS11, that synergizes with Wnt-3a ligand in the activation of Wnt/β-catenin signal transduction. Through affinity chromatography and subsequent functional assays, we showed that QS11 binds and inhibits the GTPase activating protein of ADP-ribosylation factor 1 (ARFGAP1), suggesting that QS11 modulates Wnt/β-catenin signaling through an effect on protein trafficking. Consistent with its function as an ARFGAP inhibitor, QS11 inhibits migration of ARFGAP overexpressing breast cancer cells.

Original languageEnglish
Pages (from-to)7444-7448
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number18
DOIs
StatePublished - May 1 2007

Keywords

  • ARFGAP inhibitor
  • Regenerative medicine
  • Small-molecule screen
  • Wnt signaling

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