De Novo-Designed APC/C Inhibitors Provide a Rationale for Targeting RING-Type E3 Ubiquitin Ligases.
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ICR Authors
Authors
Ruiz-Gómez, G
Uvizl, A
Bakos, G
Leung, JK
Pisabarro, MT
Mansfeld, J
Uvizl, A
Bakos, G
Leung, JK
Pisabarro, MT
Mansfeld, J
Document Type
Journal Article
Date
2025-06-12
Date Accepted
2025-04-24
Abstract
The ubiquitin system represents an attractive pharmacological target for numerous pathological processes, including cancer and neurodegeneration. RING domain-containing E3 ubiquitin ligases constitute the largest class of ubiquitin enzymes, providing a scaffold for substrate recognition and catalysis. Their shallow groove recognition interfaces involving discontinuous epitopes and a lack of defined binding pockets have largely rendered them undruggable. Inspired by natural RING inhibitors, we have developed a pharmacophore-based strategy for the rational design of peptidomimetics targeting RING domains, and we demonstrate its feasibility by using the macromolecular APC/C complex (anaphase-promoting complex/cyclosome). We designed scaffolds binding to the APC/C RING domain and efficiently inhibiting its activity in vitro. Iterative structure-based design and experimental studies to optimize their chemical stability, permeability, and specificity lead to new hydrocarbon-stapled-based molecules inhibiting APC/C in vitro and in cancer cells. Our results provide a robust rationale for targeting RING-containing enzymes of therapeutic value and promising leads for clinical APC/C inhibition.
Citation
Journal of Medicinal Chemistry, 2025, 68 (11), pp. 11468 - 11483
Source Title
Journal of Medicinal Chemistry
Publisher
AMER CHEMICAL SOC
ISSN
0022-2623
eISSN
1520-4804
Collections
Research Team
Post-transl modification