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 () and Susan K. Logan ()
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Jeffrey A. Schneider: New York University School of Medicine
Timothy W. Craven: New York University
Amanda C. Kasper: New York University
Chi Yun: New York University School of Medicine
Michael Haugbro: New York University
Erica M. Briggs: New York University School of Medicine
Vladimir Svetlov: New York University School of Medicine
Evgeny Nudler: New York University School of Medicine
Holger Knaut: New York University School of Medicine
Richard Bonneau: New York University
Michael J. Garabedian: New York University School of Medicine
Kent Kirshenbaum: New York University
Susan K. Logan: New York University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06845-3

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