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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 allow targeted protein degradation via the Ubiquitin Proteasome System.
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.
Figure 1: Schematic showing PROTACs catalytic mode of action. PROTACs allow the formation of a ternary complex between 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
Studies involving the use of PROTACs to degrade Bromo-and Extra-Terminal (BET) proteins revealed that PROTACs can select between closely related proteins. Compound MZ 1 (Cat.No. 6154), which is based on (+)-JQ1 (Cat.No. 4499) conjugated to a von Hippel-Lindau ligand, retains affinity for BRD2, BRD3 and BRD4 (Kd = 13-60 nM) but preferentially degrades BRD4 over BRD2 and BRD3. The removal of BRD4 results in the downregulation of the cancer super-controller, MYC.
PROTACs represent and exciting new modality, repurposing small molecule chemical tools to selectively degrade, rather than simply inhibit, target proteins of interest.
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