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

Aberrant activation of Wnt/beta-catenin signaling has been associated with the onset and progression of many types of tumors and thus beta-catenin represents one attractive intracellular target for cancer therapy. Based on the Axin-derived peptide that binds to beta-catenin, two stapled peptides SAHPA1 and xStAx were reported to enhance or impair Wnt/beta-catenin signaling, respectively. In this study, we designed PROTACs (proteolysis targeting chimeras) by coupling SAHPA1 or xStAx with the VHL ligand to achieve efficient beta-catenin degradation. The obtained xStAx-VHLL sustained beta-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 APC(min/+) 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 beta-catenin degrader PROTACs as a new class of promising anticancer agent.