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 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.

Wnt/β-连环蛋白信号传导的异常激活与许多类型肿瘤的发生和进展有关，因此β-连环蛋白代表了一种有吸引力的癌症治疗细胞内靶点。基于与 β-连环蛋白结合的轴蛋白衍生肽，据报道两种钉合肽 SAHPA1 和 xStAx 分别增强或损害 Wnt/β-连环蛋白信号传导。在本研究中，我们通过将 SAHPA1 或 xStAx 与 VHL 配体偶联来设计 PROTAC（蛋白水解靶向嵌合体），以实现有效的 β-catenin 降解。获得的 xStAx-VHLL 能够持续降解 β-连环蛋白，并在癌细胞和APC ^−/−类器官中表现出对 Wnt 信号传导的强烈抑制。此外，xStAx-VHLL可以有效抑制BALB/C裸鼠的肿瘤形成，并减少APC ^min/+小鼠中现有的肿瘤。更重要的是，xStAx-VHLL 可以有效抑制结直肠癌患者来源的类器官的存活。这些发现表明xStAx-VHLL具有预防和治疗癌症的能力，凸显了β-连环蛋白降解剂PROTAC作为一类新型有前景的抗癌药物的潜力。