Harnessing the cell’s natural waste disposal system

PROTACs – or PROteolysis TArgeting Chimeras – degrade unwanted or harmful proteins in cells with high specificity. They have the ability to target previously “undruggable” proteins through their unique mode of action.

PROTACs are two-headed small molecules connected by a linker, with one ‘head’ molecule that selectively binds the target protein and a second ‘head’ molecule that recruits the cellular enzyme, E3 ubiquitin ligase. Once connected to the target protein, the ligase enzyme tags the target protein for destruction in a process known as ubiquitination. The tagged target protein is subsequently degraded by the proteasome, the cell’s own waste disposal system.

Uniquely, they can act on target protein surfaces or shallow cavities with sufficient affinity to induce their degradation, allowing the exploration of novel targets that may not have well-defined drug binding sites. Lower doses of PROTACs can also be potentially effective in achieving therapeutic benefit as they rely on catalytically marking target proteins for destruction, rather than binding to and inhibiting target protein activity.

The novel mode of action of PROTACs does not depend on finding deep drug-binding cavities on target molecules that small molecules normally require. By degrading their target proteins, they also have the potential to produce a long-lasting biological effect.

Malin Lemurell Head of Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D

Our approach to the development of PROTACs is underpinned by advancements in proteomics technology. With a robust platform to enable the design and characterisation of novel PROTACs with the best chances of success in clinic, we are rapidly growing the number of projects utilising this approach across our therapeutic areas.3


1. Sun X, Gao H, Yang Y, et al. PROTACs: great opportunities for academia and industry. Signal Transduct Target Ther. 2019;4:64. Published 2019 Dec 24.

2. Konstantinidou M, Li J, Zhang B, et al. PROTACs- a game-changing technology. Expert Opin Drug Discov. 2019;14(12):1255-1268.

3. Hsu JH, Rasmusson T, Robinson J, et al. EED-Targeted PROTACs Degrade EED, EZH2, and SUZ12 in the PRC2 Complex. Cell Chem Biol. 2020;27(1):41-46.e17.

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