New Drug Candidates Target the Wnt Signaling Pathway

A team of molecular and cell biologists have isolated two classes of chemical compounds that disrupt the Wnt signaling pathway, which is associated with a broad range of diseases including Alzheimer's and polycystic kidney disease, cancer, and type II diabetes.

Wnt proteins form a family of highly conserved secreted signaling molecules that regulate cell-to-cell interactions during embryogenesis. Insights into the mechanisms of Wnt action have emerged from several systems: genetics in Drosophila and Caenorhabditis elegans, biochemistry in cell culture, and ectopic gene expression in Xenopus embryos. Mutations in Wnt genes or Wnt pathway components lead to specific developmental defects, while various human diseases, including cancer, are caused by abnormal Wnt signaling. As currently understood, Wnt proteins bind to receptors of the Frizzled and LRP families on the cell surface. Through several cytoplasmic relay components, the signal is transduced to beta-catenin, which then enters the nucleus and forms a complex with the TCF protein to activate transcription of Wnt target genes.

Investigators at the University of Texas Southwestern Medical Center (Dallas, USA) worked with a line of genetically engineered mouse cells growing in tissue culture. The cells had been modified to emit a green fluorescence when Wnt-controlled pathways were active. An automated system then screened more than 200,000 compounds to determine their ability to prevent the cells from fluorescing.

They reported in the January 4, 2009, online edition of the journal Nature Chemical Biology the isolation of two new classes of small molecules that reversibly disrupted Wnt pathway responses. One class inhibited the activity of Porcupine, a membrane-bound acyltransferase that is essential to the production of Wnt proteins, while the other prevented destruction of Axin proteins, which are suppressors of Wnt/beta-catenin pathway activity.

"The identification of these chemicals and their targets within this cellular pathway represents an important step in developing therapeutic agents," said senior author Dr. Lawrence Lum, assistant professor of cell biology at the University of Texas Southwestern Medical Center. "The ability to attack this disease pathway at two distinct regulatory steps is an important step toward realizing personalized medicine that aims to tailor the use of drugs for specific genetic mutations."

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University of Texas Southwestern Medical Center