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

  • Cell Discov. 2020 Jun 9;6:35. doi: 10.1038/s41421-020-0171-1.
Hongwei Liao   #  1 ,  Xiang Li   #  2 ,  Lianzheng Zhao   #  1 ,  Yalong Wang  1 ,  Xiaodan Wang  1 ,  Ye Wu  2 ,  Xin Zhou  3 ,  Wei Fu  3 ,  Lei Liu  4 ,  Hong-Gang Hu  2  5 ,  Ye-Guang Chen  1
Affiliations
  • 1. The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, 100084 Beijing, China.
  • 2. School of Pharmacy, Second Military Medical University, 200433 Shanghai, China.
  • 3. Department of General Surgery, Peking University Third Hospital, Beijing, China.
  • 4. Tsinghua-Peking Center for Life Sciences, Department of Chemistry, Tsinghua University, 100084 Beijing, China.
  • 5. Institute of Translational Medicine, Shanghai University, 200444 Shanghai, China.
  • # Contributed equally.
PMID: 32550000 DOI: 10.1038/s41421-020-0171-1
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.

Keywords
Drug development; Targeted therapies.
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