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.
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Supporting computational and chemical methods (including compound synthesis and NMR spectra) are described in the supplementary file, which also includes Supplementary molecular modeling results, supplementary tables, figures, movies, PDB-formatted files. The raw data generated in this study are provided in the Supplementary Source Data file. The computational source data can be accessed at https://doi.org/10.5281/zenodo.18313893. Source data are provided with this paper.
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Acknowledgements
We thank Dr. Daniel Reynes (Emory University School of Medicine) for IMPDH2 cDNA, and Dr. Scott Wilson (U. Alabama) and Dr. Min Jae Lee for Usp14‾/‾ MEFs cells, Dr. Marta Taulés (Molecular interaction analysis Technology, CCiTUB) for SPR analysis, Carles Bonet (Genomics and Transcriptomics core service, BMB) for qPCR analysis, Dr. Lluís Ribas (IRB-Barcelona) for lentiviral vectors, and Dr. Daniel Finley, Dr. Cristina Mayor-Ruiz and Dr. Jordi Casanova for their help with reagents. The authors are thankful to Dr. Adolfo Ferrando and Dr. Clara Reglero (Columbia U.) for insightful ideas, and to Dr. Gemma Triola and Dr. Ignacio Alfonso for their critical reading of the manuscript. The authors thankfully acknowledge the use of the computational resources of the Consorci de Serveis Universitaris de Catalunya (CSUC) and of the Centro de Supercomputación de Galicia (CESGA). We thank Albaha University for their funding to A.A. This work was supported with grants by Spanish Ministry of Science and Innovation (PID2020-113813RB-I00 and PID2023-146670OB-C21) and the European Commission – NextGenerationEU (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global) and Generalitat de Catalunya (2021-SGR-00504).
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MC, TR, AZ, NGS, AGA and BCM performed the biochemical and biological experiments. HC, JLA, and AA synthesized the compounds. PFN generated and provided cell lines. JB performed the computational analysis. JC, AD, JB, GF, and BC designed the research. JB, GF and BC wrote the manuscript with contributions of all authors.
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JC, JB, GF, BC, JLA, and AD are named as inventors on a patent application (PCT/EP2025/056573) claiming the use of the described 26S-UIDs for use for the treatment of cancer related to CERT1, filed by the Spanish National Research Council. The other authors declare no competing interests.
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Casasampere, M., Carneros, H., Roda, T. et al. Expanding the targeted protein degradation approach with small molecule chimeras directed to the 26S proteasome. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71132-5
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DOI: https://doi.org/10.1038/s41467-026-71132-5
