Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 44, Pages 17942-17947Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1208396109
Keywords
colorectal cancer; peptide engineering; targeted therapy
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Funding
- GlaxoSmithKline
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
- Deutsche Akademie der Naturforscher Leopoldina [LPDS 2009-2]
- Susan G. Komen for the Cure [KG091054]
- American Association for Cancer Research
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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 beta-catenin by interfering with its constitutive degradation. beta-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 beta-catenin hyperactivity, but such interactions have proven intransigent with respect to small-molecule targeting. Hence beta-catenin remains an elusive target for translational cancer therapy. Here we report the discovery of a hydrocarbon-stapled peptide that directly targets beta-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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