PROTACs Research

PROTACs (PROteolysis TArgeting Chimeras) are heterobifunctional small molecules containing binding moieties for an E3 ubiquitin ligase and a target protein joined by a linker. PROTACs induce targeted protein degradation via the Ubiquitin Proteasome System.

Targets

PROTACs (PROteolysis TArgeting Chimeras) are heterobifunctional small molecules, around 700-1000 Da in size, which induce targeted protein degradation (TPD) via the Ubiquitin Proteasome System (UPS). The UPS initiates protein degradation via the addition of ubiquitin to substrate proteins, a process performed by E3 ligases.

PROTACs consist of binding moieties for an E3 ubiquitin ligase and a target protein joined by a linker. The binding of both moieties results in the formation of a ternary complex between target protein and E3 ligase, leading to polyubiquitination of the target protein, its recognition by the proteasome and subsequent degradation.

A key feature of PROTACs is their catalytic mode of action. They dissociate following ubiquitination and rebind to new target proteins, which allows their use at sub-stoichiometric concentrations.


PROTACs - Tools for Targeted Protein Degradation

PROTACs - Tools for Targeted Protein Degradation

Figure 1: Schematic showing PROTACs catalytic mode of action. PROTACs initiate the formation of a ternary complex between an E3 ubiquitin ligase and a target protein which results in polyubiquitination of the target protein, its recognition by the proteasome and subsequent degradation. PROTACs act catalytically by repeatedly engaging and directing the ubiquitination of target molecules.

Adapted from Tinworth et al. (2016) Med.Chem.Comm. 7 2206.


PROTACs represent an exciting new modality, repurposing small molecule chemical tools to selectively degrade, rather than simply inhibit, target proteins of interest.