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Review

The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents

1
Molecular Biology Institute of Barcelona (IBMB), Spanish National Research Council (CSIC), Barcelona Science Park, 08028 Barcelona, Spain
2
IQS School of Engineering, Universidad Ramon Llull, Via Augusta 390, 08017 Barcelona, Spain
3
Research Unit on Bioactive Molecules (RUBAM), Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain
4
Unit of Pharmaceutical Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona (UB), Avda. Joan XXIII 27-31, 08028 Barcelona, Spain
*
Author to whom correspondence should be addressed.
Academic Editors: Cécile Polge and Alfred Vertegaal
Molecules 2020, 25(24), 5956; https://doi.org/10.3390/molecules25245956
Received: 27 October 2020 / Revised: 9 December 2020 / Accepted: 14 December 2020 / Published: 16 December 2020
The induction of protein degradation in a highly selective and efficient way by means of druggable molecules is known as targeted protein degradation (TPD). TPD emerged in the literature as a revolutionary idea: a heterobifunctional chimera with the capacity of creating an interaction between a protein of interest (POI) and a E3 ubiquitin ligase will induce a process of events in the POI, including ubiquitination, targeting to the proteasome, proteolysis and functional silencing, acting as a sort of degradative knockdown. With this programmed protein degradation, toxic and disease-causing proteins could be depleted from cells with potentially effective low drug doses. The proof-of-principle validation of this hypothesis in many studies has made the TPD strategy become a new attractive paradigm for the development of therapies for the treatment of multiple unmet diseases. Indeed, since the initial protacs (Proteolysis targeting chimeras) were posited in the 2000s, the TPD field has expanded extraordinarily, developing innovative chemistry and exploiting multiple degradation approaches. In this article, we review the breakthroughs and recent novel concepts in this highly active discipline. View Full-Text
Keywords: chimera; protac; targeted protein degradation; ubiquitin; proteasome; lysosome; autophagy chimera; protac; targeted protein degradation; ubiquitin; proteasome; lysosome; autophagy
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MDPI and ACS Style

Coll-Martínez, B.; Delgado, A.; Crosas, B. The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents. Molecules 2020, 25, 5956. https://doi.org/10.3390/molecules25245956

AMA Style

Coll-Martínez B, Delgado A, Crosas B. The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents. Molecules. 2020; 25(24):5956. https://doi.org/10.3390/molecules25245956

Chicago/Turabian Style

Coll-Martínez, Bernat, Antonio Delgado, and Bernat Crosas. 2020. "The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents" Molecules 25, no. 24: 5956. https://doi.org/10.3390/molecules25245956

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