Within the field of molecular pharmacology, glue degraders are emerging as one of the most promising innovations for overcoming the inherent constraints of conventional therapies. These small molecules are designed to induce the selective degradation of pathogenic proteins by harnessing the body’s endogenous cellular‑disposal mechanisms – a strategy that could potentially expand the scope of druggable targets to as much as 90 % of the human proteome.
Unlike classical inhibitors, which merely block the functional activity of the target protein, glue degraders promote its elimination by facilitating the formation of a complex between the target protein and an E3 ubiquitin ligase. This interaction tags the protein for destruction by the proteasome, effectively removing it from the cellular environment.
Proxygen, a biotechnology company, has chosen to focus its efforts precisely on this domain. It has developed a proprietary platform for the systematic discovery of glue degraders and is now on the cusp of initiating clinical trials with its first candidate – a compound aimed at a target that has, until now, been deemed undruggable. The therapeutic potential is broad and spans multiple areas, from oncology to neurodegenerative diseases, pointing to a possible paradigm shift in pharmaceutical discovery.
We had the opportunity to speak with its CEO, Bernd Boidol, to gain deeper insight into how research in this field is evolving.
Takeaways
Druggability and “Undruggable” Proteins: A Defining Challenge in Modern Pharmacology
Over the past decade, a pivotal concept has taken root in pharmacological research: druggability. The term refers to the feasibility of targeting a specific protein with a drug. Typically, these are abnormal proteins arising from genetic mutations, which play a central role in the onset and progression of various diseases. If a protein is deemed druggable, it means it can be bound and neutralised by a therapeutic agent – for instance, a monoclonal antibody. This strategy is already in use for treating a range of cancers, as well as autoimmune diseases such as Crohn’s disease, rheumatoid arthritis, and systemic lupus erythematosus, all of which involve malfunctioning proteins.
In the field of drug discovery – the scientific process through which new therapeutic compounds are identified by their ability to interact selectively with biological targets such as proteins or receptors – one of the most persistent challenges is the inability to target the vast majority of proteins implicated in serious diseases. Nearly all currently available drugs rely on a single mechanism of action: inhibiting the activity of the pathological protein. Yet this approach is applicable to only a very small subset of the human proteome. Well‑established estimates suggest that fewer than 10 % of proteins can be targeted using conventional small‑molecule inhibitors. The remaining 90 % – often referred to as undruggable – includes key therapeutic targets across oncology, neurodegeneration, and chronic inflammatory conditions.
An emerging technology offers a potential solution: glue degraders – a class of small molecules capable of inducing the selective degradation of target proteins by leveraging the cell’s intrinsic protein‑disposal machinery. Unlike PROTACs (Proteolysis‑Targeting Chimeras), which rely on bifunctional molecules, glue degraders act as allosteric modulators. They enhance the interaction between a target protein and an E3 ubiquitin ligase, thereby enabling the protein to be tagged with ubiquitin and subsequently degraded by the proteasome. Crucially, this does not require simultaneous direct binding to both components.
This mechanism sidesteps the need for accessible active sites on the target protein, meaning it could potentially target proteins that lack cavities or structural features amenable to classical drug binding. Moreover, the action of glue degraders is catalytic: a single molecule can trigger the degradation of multiple copies of the target protein, with significant implications for dosing and safety profiles.
Glue Degraders: Selective Power and Broad Target Reach
Glue degraders are distinguished by several key advantages:
- the expansion of the druggable proteome to potentially encompass nearly 100 %;
- high selectivity, even among highly conserved protein families;
- complete elimination of the target protein, yielding a more sustained effect than mere inhibition;
- a recyclable mode of action, enabling lower doses without compromising therapeutic efficacy.
The first molecules of this class to enter clinical use were thalidomide derivatives – lenalidomide and pomalidomide – which alter the substrate specificity of the E3 ligase cereblon, promoting the degradation of transcription factors involved in haematological malignancies. In recent years, however, the field has expanded significantly, fuelled by advances in screening technologies and the combined application of omics data, structural biology, and artificial intelligence.
Proxygen’s Contribution
It is within this evolving landscape that Proxygen has emerged. Founded in 2020 as a spin‑off from CeMM, the Research Center for Molecular Medicine in Vienna – one of Europe’s leading institutes for translational biomedical research and affiliated with the Austrian Academy of Sciences – the company has developed a proprietary platform for the systematic identification of glue degraders. This platform integrates molecular screening, cellular biology, and computational approaches, enabling the discovery of novel degraders with therapeutic potential.
As Bernd Boidol, CEO and co‑founder of Proxygen, explains:
«Our platform was born out of the need to overcome the limitations of the serendipitous approach traditionally used in the discovery of glue degraders. We’ve managed to bring structure and rationale to what has historically been an inefficient process, drawing on expertise developed within the academic research setting».
Today, the company has a team of 35 people and is approximately one year away from entering clinical trials with its first molecular candidate. This compound is designed to degrade a protein that, until now, has been considered entirely untreatable – a protein implicated in various cancers, including breast and gastric carcinomas. «There were no active inhibitors available for this protein», Boidol emphasises, «and that’s precisely why we believe targeted degradation could mark a therapeutic breakthrough for many patients».
Outlook and Future Applications
Beyond its first clinical candidate, Proxygen has already identified several other promising glue degraders and aims to significantly expand its pipeline to include a wide array of additional targets. Scaling up the platform remains a key strategic priority, and to that end, the company is actively exploring partnerships with major pharmaceutical firms and institutional investors.
«We are already collaborating with some of the world’s leading pharmaceutical companies. Partnerships are essential for scaling, but they must be built on solid scientific foundations and a genuine sharing of expertise», Boidol states.
The company adopts a focused, pragmatic approach to molecular modelling and artificial intelligence, steering clear of sweeping claims. «We’re not an AI company», says Boidol, «but we harness AI where it adds value – for instance, in structural analysis and predicting protein–protein interactions. That said, what’s observed in silico must always be validated in vitro and in cellulo. The feedback loop between modelling and empirical data is essential».
A Paradigm Shift for the Entire Sector
The rising interest in glue degraders is reflected not only in a growing body of recent publications but also in the increasing attention from biotech investors. A landmark study by Winter et al., published in Cell in 2015, demonstrated the ability of these molecules to target previously unreachable proteins in vivo, paving the way for large‑scale preclinical validation. The potential is such that glue degraders are now seen as a possible future mainstay of pharmacological strategy – alongside small molecules, monoclonal antibodies, and RNA‑based therapeutics.
The direction of travel is clear: to make previously untreatable pathological targets therapeutically accessible and to broaden the scope of treatable diseases – not through incremental improvements, but by ushering in a genuine technological leap. As Boidol puts it: «Our goal is easy to state, but far harder to achieve: to turn a lab‑based technology into real‑world therapies. A good idea is not enough – it takes time, rigour, and an ecosystem capable of supporting the entire development journey».
Glimpses of Futures
To better understand the future trajectories of glue degraders, we can apply the STEPS framework, which assesses the potential impact of emerging technologies across five interconnected dimensions: Social, Technological, Economic, Political, and Sustainability.
S – SOCIAL
Improved access to more effective treatments for serious, currently untreatable diseases could radically reshape the patient experience and shift societal perceptions of illnesses long considered incurable. The ability to intervene earlier and with greater precision may lighten the caregiving burden on families and healthcare systems, ultimately prompting a redefinition of care pathways.
T – TECHNOLOGICAL
Glue degrader platforms represent a new therapeutic modality – catalytic and selective – with the potential to significantly expand the boundaries of molecular pharmacology. Their integration with structural biology, high‑throughput screening, and structured AI systems is likely to accelerate the discovery of new candidates and enhance the personalisation of treatment in the coming years.
E – ECONOMIC
The economic and industrial implications are substantial. Should glue degraders achieve clinical validation, they may give rise to new therapeutic markets, while also reducing costs associated with ineffective treatments and lifelong disease management. Companies capable of developing scalable platforms will enjoy a strong competitive advantage in the biotech and pharmaceutical sectors.
P – POLITICAL
Political and regulatory challenges will focus primarily on establishing new standards for the approval and validation of protein‑degradation‑based drugs. Regulatory harmonisation across agencies will be essential to facilitate market access for these novel compounds – without compromising safety or efficacy.
S – SUSTAINABILITY
From an environmental standpoint, the use of lower doses and more targeted mechanisms of action could reduce pharmaceutical waste and the ecological toxicity burden. Furthermore, enhanced therapeutic efficacy could lead to shorter treatment cycles and more efficient use of healthcare resources, indirectly supporting the long‑term sustainability of health systems.
