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Updated: Jun 13, 2025

Using Phage Display to Develop Ubiquitin Variant Modulators for E3 Ligases
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De Novo-Designed APC/C Inhibitors Provide a Rationale for Targeting RING-Type E3 Ubiquitin Ligases.

Gloria Ruiz-Gómez1, Alena Uvizl2, Gabor Bakos2

  • 1Structural Bioinformatics, Biotechnology Center (BIOTEC), TU Dresden, 01307 Dresden, Germany.

Journal of Medicinal Chemistry
|May 21, 2025
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Summary

Researchers designed novel peptidomimetics targeting RING domains, a challenging class of enzymes. These molecules successfully inhibited the anaphase-promoting complex/cyclosome (APC/C) in cancer cells, offering new therapeutic strategies.

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Area of Science:

  • Biochemistry
  • Pharmacology
  • Structural Biology

Background:

  • The ubiquitin system is crucial in cellular processes and a target for diseases like cancer.
  • RING domain-containing E3 ubiquitin ligases are abundant but difficult to drug due to their shallow binding sites.
  • The anaphase-promoting complex/cyclosome (APC/C) is a key E3 ligase involved in cell cycle regulation.

Purpose of the Study:

  • To develop a rational design strategy for targeting RING domains with peptidomimetics.
  • To create novel inhibitors for the APC/C complex.
  • To validate these inhibitors in cancer cells.

Main Methods:

  • Pharmacophore-based design inspired by natural RING inhibitors.
  • Structure-based iterative design and optimization of peptidomimetics.
  • In vitro biochemical assays and cell-based studies to assess APC/C inhibition.

Main Results:

  • Designed scaffolds that bind to the APC/C RING domain and inhibit its activity.
  • Developed hydrocarbon-stapled peptidomimetics with improved stability, permeability, and specificity.
  • Demonstrated APC/C inhibition by these molecules in vitro and in cancer cells.

Conclusions:

  • A successful strategy for rational design of RING domain inhibitors was established.
  • Novel peptidomimetics targeting APC/C show therapeutic potential for cancer treatment.
  • This work provides a foundation for targeting other therapeutically relevant RING-containing enzymes.