PROTACs and Molecular Glues – drugging the ‘undruggable’

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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.

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.2

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

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

Our automated end-to-end platform is accelerating the discovery of orally bioavailable PROTAC drug molecules, and we have established a suite of pharmacology and safety assays that allow us to monitor protein degradation and predict disease efficacy.

Ian Storer, VP Hit Discovery, Discovery Sciences, BioPharmaceuticals R&D

Molecular Glues 
Beyond PROTACs we are exploring the potential of molecular glues, another promising drug modality that leverages chemically-induced proximity in the cell 5. Molecular glues are small molecules that mediate the interaction between a protein of interest and cellular enzyme such as Cyclophilin A or E3 ligases, to promote the recruitment of additional protein partners and inactive the target protein or drive it’s degradation in a manner similar to PROTACs respectively. Both PROTACs and molecular glues are exciting precision medicines that can potentially address disordered proteins in cancer that were previously considered undruggable targets.5

Currently, cancer therapies only target a small fraction of biologically validated targets. By expanding our drug discovery toolkit to emerging modalities such as PROTACs and molecular glues, we have the opportunity to reach important oncology targets that were previously considered undruggable using traditional approaches.

David Wilson, Vice President, Global Head of Oncology Chemistry

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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.

4. Pike A, Williamson B et al., Optimising proteolysis-targeting chimeras (PROTACs) for oral drug delivery: a drug metabolism and pharmacokinetics perspective. Drug Discov Today. 2020; 25(10):1793-1800.; Moreau K, Coen M et al. Proteolysis‐targeting chimeras in drug development: A safety perspective. J Pharmacol. 2020;177:1709–1718 

5. Schreiber SL,  The Rise of Molecular Glues. Cell, 2021 Jan 7;184(1):3-9.

Veeva ID: Z4-40997
Date of preparation: January 2022