Expanding the targeted protein degradation approach with small molecule chimeras directed to the 26S proteasome

Classical proteolysis targeting chimeras (Protacs) bind specific targets and E3 ubiquitin-ligases, promoting ubiquitination and degradation of targets by the proteasome. Multiple chimeras that degrade proteins relevant in several diseases have been developed, and the number is quickly increasing, indicating their therapeutic projection. Given the specificities of proteolytic pathways and limitations in E3-based Protacs, alternative strategies in targeted protein degradation are pursued. Herein, using two targets relevant in oncology as models (IMPDH2 and CERT1), we provide proof of concept for 26S-oriented compounds based on small-molecule ligands of USP14, a 26S-associated deubiquitinase involved in substrate processing and allosteric regulation of 26S activity. Our findings will expand the potential of targeted protein degradation.

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Publication Details

Journal
Nature Communications
Published
2026-03-28
DOI
https://doi.org/10.1038/s41467-026-71132-5
Primary Topic
Protein Degradation and Inhibitors
Type
article
Field-Weighted Citation Impact
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article

Expanding the targeted protein degradation approach with small molecule chimeras directed to the 26S proteasome

Bernat Crosas, Mireia Casasampere, Gemma Fabriàs, Héctor Carneros et al.
Nature Communications
Protein Degradation and Inhibitors
article

Expanding the targeted protein degradation approach with small molecule chimeras directed to the 26S proteasome

Bernat Crosas, Mireia Casasampere, Gemma Fabriàs, Héctor Carneros, Jordi Bujons, Bernat Coll-Martínez, Abdulateef Alqahtani, Núria Gallisà-Suñé, Antonio Delgado, Alice Zuin, Josefina Casas, José Luis Abad, Tania Roda, Patricia Fernández-Nogueira, Alba González-Artero
article en

Abstract

Classical proteolysis targeting chimeras (Protacs) bind specific targets and E3 ubiquitin-ligases, promoting ubiquitination and degradation of targets by the proteasome. Multiple chimeras that degrade proteins relevant in several diseases have been developed, and the number is quickly increasing, indicating their therapeutic projection. Given the specificities of proteolytic pathways and limitations in E3-based Protacs, alternative strategies in targeted protein degradation are pursued. Herein, using two targets relevant in oncology as models (IMPDH2 and CERT1), we provide proof of concept for 26S-oriented compounds based on small-molecule ligands of USP14, a 26S-associated deubiquitinase involved in substrate processing and allosteric regulation of 26S activity. Our findings will expand the potential of targeted protein degradation.

Nature Communications
Instituto de Salud Carlos III (ES), Centro Nacional de Microbiologia (ES), Institute for Research in Biomedicine (ES), Institute of Advanced Chemistry of Catalonia (ES), Unidad Funcional de Investigación de Enfermedades Crónicas (ES), Institut de Biologia Molecular de Barcelona (ES), Universitat de Barcelona (ES)
Openalex Percentile: Top 4%
Protein Degradation and Inhibitors
DOIOpen Access PDFOpenAlex
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