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

Jeffrey A. Schneider, Timothy W. Craven, Amanda C. Kasper, Chi Yun, Michael Haugbro, Erica M. Briggs, Vladimir Svetlov, Evgeny Nudler, Holger Knaut, Richard Bonneau, Michael J. Garabedian, Kent Kirshenbaum, Susan K. Logan

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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.

Original languageEnglish (US)
Article number4396
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Schneider, J. A., Craven, T. W., Kasper, A. C., Yun, C., Haugbro, M., Briggs, E. M., Svetlov, V., Nudler, E., Knaut, H., Bonneau, R., Garabedian, M. J., Kirshenbaum, K., & Logan, S. K. (2018). Design of Peptoid-peptide Macrocycles to Inhibit the β-catenin TCF Interaction in Prostate Cancer. Nature communications, 9(1), [4396]. https://doi.org/10.1038/s41467-018-06845-3