Brandon Czowski (University of Notre Dame)

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Location: 201 DeBartolo Hall

 Abstract:  Aberrant activation of Wnt/β-catenin signaling has been associated with the onset and progression of many types of tumors and thus β-catenin represents one attractive intracellular target for cancer therapy. Based on the Axin-derived peptide that binds to β-catenin, two stapled peptides SAHPA1 and xStAx were reported to enhance or impair Wnt/ β-catenin signaling, respectively. In this study, we designed PROTACs (proteolysis targeting chimeras) by coupling SAHPA1 or xStAx with the VHL ligand to achieve efficient β-catenin degradation. The obtained xStAx-VHLL sustained β-catenin degradation and manifested strong inhibition of Wnt signaling in cancer cells and in APC−/− organoids. Furthermore, xStAx-VHLL could effectively restrain tumor formation in BALB/C nude mice and diminish the existing tumors in APCmin/+ mice. More importantly, xStAx-VHLL could potently inhibit the survival of colorectal cancer patient-derived organoids. These findings suggest that xStAx-VHLL exhibits the ability of cancer prevention and cure, highlighting the potential of β-catenin degrader PROTACs as a new class of promising anticancer agent.1

  1. Liao, H., Li, X., Zhao, L., Wang, Y., Wang, X., Wu, Y., Zhou, X., Fu, W., Liu, L., Hu, H. G., & Chen, Y. G. (2020). A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer. Cell Discovery, 6(1), 1–12. https://doi.org/10.1038/s41421-020-0171-1

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