PROTAC technology: A new drug design for chemical biology with many challenges in drug discovery

Guedeney, N; Cornu, M; Schwalen, F; Kieffer, C; Voisin-Chiret, AS

Abstract

Target Protein Degradation TPD is a new avenue and revolutionary for therapeutics because redefining the principles of classical drug discovery and guided by event-based target activity rather than the occupancy-driven activity. Since the discovery of the first PROTAC in 2001, TPD represents a rapidly growing technology, with applications in both drug discovery and chemical biology. Over the last decade, many questions have been raised and today the knowledge gained by each team has elucidated a number of them, although there is still a long way to go. The objective of this work is to present the challenges that the PROTAC strategy has very recently addressed in drug design and discovery by presenting extremely recent results from the literature and to provide guidelines in the drug design of new PROTACs as successful therapeutic modality for medicinal chemists.

Keywords: PROteolysis Targeting Chimera (PROTAC); Ubiquitin-mediated proteasomal degradation system (UPS); E3 ubiquitin ligase; Medicinal chemistry

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PROTAC

Proteolysis Targeting Chimeras, or PROTACs, represent a groundbreaking advancement in the field of drug discovery. These innovative small molecules are designed to eliminate specific disease-causing proteins by leveraging the cell's natural degradation system. Unlike traditional drugs that merely inhibit the function of harmful proteins, PROTACs offer a more dynamic approach by marking these proteins for destruction, thus preventing them from exerting their detrimental effects. The PROTAC technology works by binding to both the target protein and an E3 ubiquitin ligase, a component of the cell’s protein disposal system. This binding leads to the tagging of the target protein with ubiquitin molecules, signaling for its degradation by the proteasome, the cell's waste disposal unit. This unique mechanism allows PROTACs to target proteins that were previously considered "undruggable," opening up new avenues for therapeutic intervention. In drug discovery, PROTACs hold immense potential. They can be designed to target a wide range of proteins involved in various diseases, including cancer, neurodegenerative disorders, and infectious diseases. By offering a novel way to tackle these proteins, PROTACs could lead to the development of more effective and long-lasting treatments. As research progresses, the application of PROTAC technology is poised to revolutionize how we approach drug development and disease management.