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A beginner’s guide to current synthetic linker strategies towards VHL-recruiting PROTACs

Lookup NU author(s): Nikol Zografou Barredo, Dr Alex Hallatt, Dr Jennyfer Goujon-RicciORCiD, 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.

Publication metadata

Author(s): Zografou-Barredo NA, Hallatt A, Goujon-Ricci J, Cano C

Publication type: Review

Publication status: Published

Journal: Bioorganic & Medicinal Chemistry

Year: 2023

Volume: 88-89

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


DOI: 10.1016/j.bmc.2023.117334