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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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1 Departments of Urology, New York University School of Medicine, New York, NY, USA
2 Department of Chemistry, New York University, New York, NY, USA; Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY, USA
3 Department of Chemistry, New York University, New York, NY, USA
4 Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY, USA
5 Departments of Urology, New York University School of Medicine, New York, NY, USA; Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA
6 Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA; Howard Hughes Medical Institute, New York University School of Medicine, New York, NY, USA
7 Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY, USA
8 Microbiology, New York University School of Medicine, New York, NY, USA; Departments of Urology, New York University School of Medicine, New York, NY, USA