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Nat Commun. 2018 Oct 23;9(1):4396. doi: 10.1038/s41467-018-06845-3.

Design of Peptoid-peptide Macrocycles to Inhibit the β-catenin TCF Interaction in Prostate Cancer.

Author information

1
Departments of Urology, New York University School of Medicine, New York, NY, 10016, USA.
2
Department of Chemistry, New York University, New York, NY, 10003, USA.
3
Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY, 10003, USA.
4
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY, 10016, USA.
5
Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.
6
Howard Hughes Medical Institute, New York University School of Medicine, New York, NY, 10016, USA.
7
Microbiology, New York University School of Medicine, New York, NY, 10016, USA.
8
Department of Chemistry, New York University, New York, NY, 10003, USA. kk54@nyu.edu.
9
Departments of Urology, New York University School of Medicine, New York, NY, 10016, USA. Susan.Logan@nyulangone.org.
10
Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA. Susan.Logan@nyulangone.org.

Abstract

New chemical inhibitors of protein-protein interactions are needed to propel advances in molecular pharmacology. Peptoids are peptidomimetic oligomers with the capability to inhibit protein-protein interactions by mimicking protein secondary structure motifs. Here we report the in silico design of a macrocycle primarily composed of peptoid subunits that targets the β-catenin:TCF interaction. The β-catenin:TCF interaction plays a critical role in the Wnt signaling pathway which is over-activated in multiple cancers, including prostate cancer. Using the Rosetta suite of protein design algorithms, we evaluate how different macrocycle structures can bind a pocket on β-catenin that associates with TCF. The in silico designed macrocycles are screened in vitro using luciferase reporters to identify promising compounds. The most active macrocycle inhibits both Wnt and AR-signaling in prostate cancer cell lines, and markedly diminishes their proliferation. In vivo potential is demonstrated through a zebrafish model, in which Wnt signaling is potently inhibited.

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