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Lookup NU author(s): Dr Natalia Zografou-Barredo,
Dr Jennyfer Goujon-Ricci,
Dr Celine CanoORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Over the last two decades, proteolysis targeting chimeras (PROTACs) have been revolutionary in drug development rendering targeted protein degradation (TPD) as an emerging therapeutic modality. These heterobifunctional molecules are comprised of three units: a ligand for the protein of interest (POI), a ligand for an E3 ubiquitin ligase, and a linker that tethers the two motifs together. Von Hippel-Lindau (VHL) is one of the most widely employed E3 ligases in PROTACs development due to its prevalent expression across tissue types and well-characterised ligands. Linker composition and length has proven to play an important role in determining the physicochemical properties and spatial orientation of the POI-PROTAC-E3 ternary complex, thus influencing the bioactivity of degraders. Numerous articles and reports have been published showcasing the medicinal chemistry aspects of the linker design, but few have focused on the chemistry around tethering linkers to E3 ligase ligands. In this review, we focus on the current synthetic linker strategies employed in the assembly of VHL-recruiting PROTACs. We aim to cover a range of fundamental chemistries used to incorporate linkers of varying length, composition and functionality.
Author(s): Zografou-Barredo NA, Hallatt A, Goujon-Ricci J, Cano C
Publication type: Review
Publication status: Published
Journal: Bioorganic & Medicinal Chemistry
Print publication date: 06/06/2023
Online publication date: 18/05/2023
Acceptance date: 12/05/2023
ISSN (print): 0968-0896
ISSN (electronic): 1464-3391