PROTACs and Molecular Glues – drugging the ‘undruggable’

Throughout the last decade, researchers have made great progress studying how the proximity, or physical closeness, of proteins inside a cell influences processes like transcription, signalling and protein folding. Scientists are now exploring small molecules with unique modes of action that can influence this proximity and related processes in cancer cells to address previously “undruggable” targets.¹ Major investments in novel technologies have helped usher these compounds into the clinic, with the expectation that they could transform the treatment landscape for patients with cancer.

PROteolysis TArgeting Chimeras – or PROTACs – are highly specific medicines that degrade unwanted or harmful proteins in cells. PROTACs are bifunctional molecules with two heads connected by a linker. One ‘head’ of the molecule selectively binds the target protein and a second ‘head’ of the molecule recruits a cellular enzyme, an E3 ubiquitin ligase. This enables the PROTAC to bring the ligase enzyme into close contact with the target protein, enabling the protein to be labelled with a ubiquitin tag and targeted for degradation by the ubiquitin-proteasome system. This process utilises the cell’s natural waste disposal system, resulting in the protein being eliminated from the cell.

PROTACs have a unique ability to target binding sites on protein surfaces or shallow cavities that are otherwise unreachable by other drug modalities, allowing the exploration of novel targets.¹ In addition, because their mode of action results in protein degradation, PROTACs can drive a differentiated pharmacological response versus traditional small molecule inhibitors.

Our advancements in proteomics technology underpins the development of PROTACs as therapeutics. With a robust platform to enable the efficient design and characterisation of novel PROTACs , we are rapidly growing the number of projects utilising this approach across our therapy areas.^{3, 4}