Breaking through the undruggable barrier with TPDs

Alex Bentley, an 1851 Industrial Fellow working with GSK and the University of Strathclyde, discusses how his research into protein degraders will benefit drug discovery efforts across the pharmaceutical industry. 

First proposed in the early 2000s, targeted protein degradation (TPD) has emerged as a therapeutic modality with the potential to transform the treatment of disease associated with previously intractable biological targets. The human genome encodes more than 20,000 proteins, many of which have historically been considered “undruggable” due to the absence of well-defined binding pockets or enzymatic activity that can be readily inhibited by conventional small molecules. As a result, a significant proportion of disease-causing proteins, particularly those involved in cancer and inflammatory diseases, remain inadequately treated by existing therapies.  

Rather than modulating protein function through inhibition, TPD seeks to eliminate disease-causing proteins entirely from the cell. This shift in approach is enabled by hijacking the ubiquitin-proteasome system (UPS), the cell’s primary pathway for regulating protein turnover. Under normal physiological conditions, the UPS maintains cellular homeostasis by attaching a molecule “tag” known as ubiquitin to unwanted or damaged proteins, marking them for degradation by the proteasome. TPD technologies exploit this system by redirecting it towards proteins of therapeutic interest. 

Protein degraders function by recruiting an E3 ubiquitin ligase and a target protein together to form a three-part complex known as a ternary complex. This complex facilitates the tagging of the target protein with ubiquitin — a process called ubiquitination — which leads to its subsequent proteasomal degradation. As degraders act catalytically, each molecule can trigger the degradation of multiple copies of the target protein; this mechanism can lead to sustained biological effects at lower drug exposures compared with traditional inhibitors.  

Two principal classes of small-molecule degraders are primarily used in drug discovery: proteolysis-targeting chimeras (PROTACs) and molecular glue degraders. Although both rely on the same proteasome-mediated degradation pathway, they differ in structure, mechanism and design strategy.  

PROTACs are bifunctional molecules composed of two distinct ligands connected by a chemical linker. One ligand binds the target protein, while the other binds the enzyme E3 ubiquitin ligase. By physically bringing these two components together, PROTACs promote the formation of the ternary complex required for ubiquitination. The modular nature of PROTACs has made them attractive from a rational design perspective, allowing researchers to combine known ligands for targets and ligases in a systematic way. However, their relatively large molecular size can present challenges related to cellular permeability, pharmacokinetics and oral bioavailability. 

Molecular glue degraders, by contrast, are typically smaller and structurally simpler. Rather than acting as a bridge for two proteins, they function by stabilising or promoting an interaction between an E3 ligase and a target protein, which otherwise would not interact. By doing this, the small molecule effectively reprogrammes the ligase to recognise a new substrate. Due to molecular glue degraders often resembling small molecules in size and physicochemical properties, this may offer advantages in terms of drug-like behaviour. 

The earliest examples of molecular glue degraders were identified retrospectively through clinical observations rather than rational drug design. In the late 1990s and early 2000s, drugs such as thalidomide and its derivatives were shown to have therapeutic effects in cancer and inflammatory diseases, despite limited understanding of their mechanism of action. It was not until 2010 that these compounds were discovered to bind the E3 ligase cereblon, altering its substrate specificity and triggering degradation of previously stable proteins. This finding provided the first clear demonstration that small molecules could redirect the UPS in a selective and therapeutically meaningful manner. 

Since then, interest in molecular glue degraders has grown, driven by advances in structural biology, chemical biology and proteomics. These tools have revealed that E3 ligases enable small molecules to reshape protein-protein interfaces and induce selective degradation. Nevertheless, the discovery of molecular glues remains challenging, as their activity is often difficult to predict and has historically relied on serendipitous approaches. Despite these challenges, TPD continues to gain momentum as a complementary strategy to traditional inhibition-based drug discovery.  

While TPD offers a powerful alternative to conventional inhibition-based drug discovery, its broader application is constrained by challenges around selectivity, off-target activity and the efficiency with which new degraders can be discovered and optimised. Addressing these challenges has become an increasingly important focus of research, particularly as the field moves beyond a small number of well-characterised targets and ligands.  

My PhD research, which is conducted in a long-standing and thriving industry/academia collaboration between GSK and the University of Strathclyde, seeks to address these limitations through two complementary projects: firstly, by investigating the mechanisms underlying off-target degradation in TPD, and secondly, by developing high-throughput approaches to degrader discovery. This research is supported by a fellowship from the Royal Commission for the Exhibition of 1851, which aims to promote fundamental scientific research with long-term industrial relevance. 

The first phase of my research has focused on understanding the behaviour of an essential translation termination factor, namely GSPT1 (G1 to S Phase Transition 1), which has emerged as a recurring off-target in degrader discovery programmes. Although GSPT1 has been explored as a therapeutic target in specific disease areas, it also plays an essential role in normal cellular protein synthesis. As a result, its unintended degradation can lead to cytotoxic effects and complicate the interpretation of biological data. 

In several TPD programmes, particularly those employing cereblon-recruiting ligands, apparent degradation of short-lived, disease-relevant proteins has later been explained by indirect effects arising from depletion of GSPT1. By disrupting global protein synthesis, off-target degradation can reduce the levels of short-lived proteins, creating misleading degradation data. This phenomenon represents a significant challenge for degrader discovery, as it can lead to the optimisation of compounds which do not degrade the intended protein. 

To address this issue systematically, I have carried out an extensive structure-activity relationship (SAR) study, involving the design, synthesis and biological evaluation of a significant library of molecular glue degraders. This dataset enabled detailed analysis of how specific chemical features influence off-target degradation of GSPT1. Variations in molecule design, including heterocyclic motifs, exit vectors, linker composition and steric environment were explored to identify structural elements that promote or suppress undesired engagement of essential proteins.  

The resulting SAR information provides practical design principles which can be used to minimise off-target degradation of GSPT1 in future degrader programmes. More broadly, the study highlights the importance of understanding off-target effects as a predictable and mechanistically driven outcome of degrader chemistry, rather than a rare or incidental observation.  

Building on this foundation, the second phase of my research has shifted towards improving efficiency and scalability of degrader discovery. Traditional degrader development is often limited by iterative synthesis and testing cycles, which can be particularly slow when exploring new ligases or large areas of chemical space. To overcome this limitation, my current project adopts a high-throughput direct-to-biology approach. 

This work focusses on a less well-investigated E3 ubiquitin ligase, expanding the toolbox of ligases available for targeted protein degradation. By combining this ligase with a direct-to-biology synthetic platform, large libraries of degraders can be generated rapidly and screened without the need for extensive purification. This approach enables thousands of compounds to be synthesised and tested in parallel, significantly accelerating early-stage discovery and improving efficiency. Biological screening is carried out using HiBiT-based assays, which allow quantitative measurement of protein degradation in live cells, providing a sensitive and physiologically relevant readout of degrader activity. 

Together, these two projects address two critical barriers facing the TPD field: investigating off-target effects and the rapid exploration of new chemical and biological space. By combining a deeper understanding of degrader behaviour with high-throughput discovery approaches, this research contributes to a more informed and efficient approach to degrader design.  

With multiple TPD therapies now progressing through late-stage clinical development, the first degrader-based medicines are expected to reach patients in the near future. As these therapies enter clinical practice, targeted protein degradation is poised to move from a promising emerging modality to an established component of modern drug discovery.  

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