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

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 APC min/+ mice. More importantly, xStAx-VHLL could potently inhibit the survival of colorectal cancer patientderived 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.

Oxysterol-binding protein-like 2 contributes to the developmental progression of preadipocytes by binding to β-catenin

“…Through the degradation pathway, β-catenin is first bound to APC and AXIN to form a complex and is then phosphorylated; finally, it is ubiquitinated and degraded by the proteasome 31 , 32 . The level of β-catenin was detected to be decreased in the KO cells, while the level of PPAR-γ was increased (Fig.…”

The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination

“…Our group has also previously used stapled peptides as PPI inhibitor to regulate Axin-β-catenin interaction with better structural stability, protease resistance and stronger efficacy of Axin (469-482) than linear peptides 102 . On this basis, we subsequently reported a new p-PROTAC with stapled technology (xStAx-VHLL) that effectively inhibited Wnt-dependent intestinal cancer in mice and the survival of colorectal cancer patient-derived organoids through degradation of β-catenin 105 . These findings strongly corroborate that constrained conformation exhibits the ability to promote the drug-like property of p-PROTAC.…”

“…Moreover, we expect that multifunctional drug delivery systems (DDS) can be regarded as novel approaches to improve therapeutic utility of p-PROTAC or achieve combination therapy. Meanwhile, the development of novel preclinical tumor models, including patient-derived organoids (PDO) and patient-derived xenografts (PDX), provides tools to better evaluate the efficacy and side effects of p-PROTACs 105 , 115 . However, the compositional complexity of p-PROTACs makes it being drug-like more challenge than simple peptides drugs, including the increased technical difficulties in evaluation of drug pharmacokinetics, stability, safety, and especially the unique catalytic cycle manner for p-PROTACs.…”

Direct targeting of β‐catenin in the Wnt signaling pathway: Current progress and perspectives

“…This approach may be more interesting than the disruption of the challenging PPIs. A PROTAC peptide (xStAx‐VHLL) has been reported by connecting stapled peptide StAx‐35R with the Von Hippel–Lindau (VHL) ligand 128 . xStAx‐VHLL achieved durable β ‐catenin degradation and impaired Wnt/ β ‐catenin signaling in cancer cells.…”