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Optimization of Peptidomimetics as Selective Inhibitors for the β-Catenin/T-Cell Factor Protein-Protein Interaction

Zhen Wang1, Min Zhang1, Jin Wang1

  • 1Drug Discovery Department , H. Lee Moffitt Cancer Center and Research Institute , Tampa , Florida 33612-9497 , United States.

Journal of Medicinal Chemistry
|March 12, 2019
PubMed

Insights

New compounds effectively disrupt the β-catenin/T-cell factor (Tcf) protein-protein interaction, a key driver in many cancers. Compound 56 shows promise in inhibiting cancer cell viability and migration by targeting this critical signaling pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • The β-catenin/T-cell factor (Tcf) protein-protein interaction (PPI) is crucial in the β-catenin signaling pathway, frequently hyperactivated in cancers and fibroses.
  • Targeting this PPI offers a therapeutic strategy for Wnt/β-catenin-driven diseases.

Purpose of the Study:

  • To develop novel small molecules that inhibit the β-catenin/Tcf PPI.
  • To evaluate the efficacy of these compounds in cancer cells with hyperactive Wnt/β-catenin signaling.

Main Methods:

  • Structure-activity relationship studies were performed based on a lead compound targeting the β-catenin Tcf4 binding site.
  • In vitro assays measured inhibition constants (Ki) for β-catenin/Tcf PPI disruption and selectivity over other PPIs.
  • Cell viability (MTS assay), PPI disruption, signaling pathway activity, and cancer cell migration/invasion were assessed in cell-based studies.

Main Results:

  • Compounds 53 and 57 were identified as potent inhibitors of the β-catenin/Tcf PPI with Ki values of 0.64 and 0.44 μM, respectively.
  • These compounds demonstrated selectivity for β-catenin/Tcf PPI over interactions with E-cadherin and APC.
  • Compound 56, an ethyl ester of 53, significantly inhibited Wnt/β-catenin-hyperactive cancer cell viability, suppressed signaling, and reduced cell migration and invasiveness.

Conclusions:

  • Novel compounds targeting the β-catenin/Tcf PPI were successfully developed.
  • Compound 56 exhibits potent anti-cancer activity by disrupting the β-catenin/Tcf interaction and inhibiting downstream signaling pathways.
  • These findings support the therapeutic potential of targeting the β-catenin/Tcf PPI in cancer treatment.

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