A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer.

Cell Discovery
Hongwei LiaoYe-Guang Chen

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.

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Citations

May 19, 2021·Cell Chemical Biology·Kusal T G Samarasinghe, Craig M Crews
Aug 17, 2020·Chemical Reviews·Xiang LiHong-Gang Hu
Nov 24, 2021·Journal of Medicinal Chemistry·Guoshun LuoHua Xiang

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Methods Mentioned

BETA
xenograft
immunoprecipitation
isothermal
pulldown
exon sequencing
xenografts
ubiquitination
PCR

Software Mentioned

GraphPad Prism
xStAx
PROTAC
VHLL
ImageJ

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