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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Embryo, Nonmammalian / metabolism
  • Eye / embryology
  • HEK293 Cells
  • Humans
  • Macrocyclic Compounds / pharmacology*
  • Male
  • Peptides / pharmacology*
  • Peptoids / pharmacology*
  • Phenotype
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Protein Binding / drug effects
  • Receptors, Androgen / metabolism
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / pathology
  • TCF Transcription Factors / metabolism*
  • Wnt Signaling Pathway
  • Zebrafish / embryology
  • beta Catenin / metabolism*

Substances

  • Macrocyclic Compounds
  • Peptides
  • Peptoids
  • Receptors, Androgen
  • TCF Transcription Factors
  • beta Catenin