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

  • Nat Commun. 2018 Oct 23;9(1):4396. doi: 10.1038/s41467-018-06845-3.
Jeffrey A Schneider  1 ,  Timothy W Craven  2  3 ,  Amanda C Kasper  2 ,  Chi Yun  4 ,  Michael Haugbro  2 ,  Erica M Briggs  1  5 ,  Vladimir Svetlov  5  6 ,  Evgeny Nudler  5  6 ,  Holger Knaut  4 ,  Richard Bonneau  3 ,  Michael J Garabedian  1  7 ,  Kent Kirshenbaum  8 ,  Susan K Logan  9  10
Affiliations
  • 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. [email protected].
  • 9. Departments of Urology, New York University School of Medicine, New York, NY, 10016, USA. [email protected].
  • 10. Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA. [email protected].
PMID: 30352998 DOI: 10.1038/s41467-018-06845-3
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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