T.N.Grossmann
et al.
(2012).
Inhibition of oncogenic Wnt signaling through direct targeting of β-catenin.
Proc Natl Acad Sci U S A,
109,
17942-17947.
PubMed id: 23071338
Aberrant activation of signaling by the Wnt pathway is strongly implicated in
the onset and progression of numerous types of cancer. Owing to the persistent
dependence of these tumors on Wnt signaling for growth and survival, inhibition
of this pathway is considered an attractive mechanism-based therapeutic
approach. Oncogenic activation of Wnt signaling can ensue from a variety of
distinct aberrations in the signaling pathway, but most share the common feature
of causing increased cellular levels of β-catenin by interfering with its
constitutive degradation. β-Catenin serves as a central hub in Wnt signaling by
engaging in crucial protein-protein interactions with both negative and positive
effectors of the pathway. Direct interference with these protein-protein
interactions is a biologically compelling approach toward suppression of
β-catenin hyperactivity, but such interactions have proven intransigent with
respect to small-molecule targeting. Hence β-catenin remains an elusive target
for translational cancer therapy. Here we report the discovery of a
hydrocarbon-stapled peptide that directly targets β-catenin and interferes with
its ability to serve as a transcriptional coactivator for T-cell factor (TCF)
proteins, the downstream transcriptional regulators of the Wnt pathway.
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