A significant proportion of E3 ligases are multiprotein complexes and are usually composed of a Sc and SBD, bound via Ad. PROTACs act as adapter molecules between the E3 ligase and any chosen POI, hijacking the activity of the cell’s natural protein degradation machinery, i.e. This brings the E2 ligase into proximity to the POI (iii) this leads to the transfer of multiple Ub units to surface exposed lysine residues (iv) the resulting polyubiquitin chain is recognised by the proteasome, leading to the proteolytic degradation of the POI and (v) the PROTAC is released and can catalyse the transfer of Ub to additional POIs (i) Ub transfer from E1 to E2 by trans-thioesterification is followed by complex formation with an E3 ligase (ii) the PROTAC binds to both the E3 ligase and POI to form a TC, where the E3 ligase is shown as an assembly of scaffolding proteins (Sc), adapter proteins (Ad), and a SBD. mechanism of PROTAC-mediated target degradation via RING-type E3 ligases. The E3 ligase targeting “anchor” (blue) is connected to the specific POI targeting warhead (green) via a variable linker B. In particular, the authors believe that advances in computational and structural methods will play an essential role to gain a better understanding of the structure and dynamics of PROTAC ternary complexes, and will be essential to address the current gaps in knowledge associated with PROTAC design.Ī. The authors highlight important limitations associated with the traditional “trial and error” approach around linker design and selection, and suggest potential future avenues to further inform rational linker design and accelerate the identification of optimised PROTACs. Finally, the authors provide a critical analysis of current strategies for PROTAC assembly. Here, the authors provide a timely overview of the diverse linker classes in the published literature, along with their underlying design principles and overall influence on the properties and bioactivity of the associated PROTACs.
This promises to unlock a wealth of novel PROTAC agents with enhanced bioactivity for therapeutic intervention. While linker design has historically received limited attention, the PROTAC field is evolving rapidly and currently undergoing an important shift from synthetically tractable alkyl and polyethylene glycol to more sophisticated functional linkers. It has become increasingly clear that the length and composition of the linker play critical roles on the physicochemical properties and bioactivity of PROTACs. Targeted protein degradation by PROTACs has emerged as a new modality for the knock down of a range of proteins, with the first agents now reaching clinical evaluation. PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands an “anchor” to bind to an E3 ubiquitin ligase and a “warhead” to bind to a protein of interest, connected by a chemical linker.
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