A Q&A with Molecular Glue Hunter Pim de Vink on the current challenges and opportunities in this rapidly evolving field of research
Molecular glues are redefining how we approach drug discovery, enabling the targeting of proteins once considered “undruggable.” Unlike traditional small molecules that bind directly to a single protein, molecular glues act as mediators, stabilizing interactions between two proteins to drive a specific biological outcome. This breakthrough mechanism is particularly valuable for targeted protein degradation (TPD) and other therapeutic applications where conventional drugs fall short.
However, discovering effective molecular glues remains a major challenge. In this interview with Pim de Vink, a molecular glue specialist from our dedicated discovery facility in the Netherlands, we explore why molecular glues are such an exciting area of research, challenges to their discovery, and strategies for progressing their discovery and development.
Q: Pim, can you briefly tell us why molecular glues represent such an exciting opportunity for drug developers?
PDV: Molecular glues open up entirely new therapeutic possibilities by enabling the modulation of protein-protein interactions that were previously inaccessible. Instead of inhibiting proteins or their interactions, as in traditional medicinal chemistry, molecular glues can induce new or enhance existing interaction between proteins, thereby creating new biology or turning existing interactions on. For example, in Targeted Protein Degradation (TPD), an interaction is induced between the target of interest and an E3 ligase, which then ubiquitinates the protein, ultimately resulting in the degradation of the target protein.
Q: In what way do glues create new accessibility for more challenging proteins?
PDV: Beyond degradation, the ability to create interactions, essentially acting as molecular matchmaking, opens vast opportunities in all kinds of pathway settings, which I personally find very exciting. Looking at it more mechanistically, targeting a complex of proteins instead of a single one allows drug developers to address proteins that lack well-defined binding pockets. This is especially relevant for intrinsically disordered proteins, which can be stabilized as part of a protein complex. Targets that are traditionally hard to drug are also good candidates for a glue approach.
Q: What exactly makes ‘undruggable’ targets good candidates for molecular glues?
PDV: Because many disease-relevant proteins lack those well-defined binding pockets, they are difficult to target with conventional small molecules. Molecular glues address this challenge by stabilizing protein-protein complexes rather than requiring a single high-affinity binding site.
Cooperativity, or ‘enhancing potential’, plays a crucial role here. Because cooperativity works both ways, a glue’s binding affinity is significantly enhanced when both protein partners are present. Furthermore, a molecular glue does not need to compete with a natural binder, it works with the system rather than against it, allowing for effective targeting even at lower affinity levels.
Q: Molecular glues have a reputation for being very challenging to discover. Do you agree with that?
PDV: Molecular glues do have that reputation, but fortunately, this perception is slowly changing. The main challenge in discovering new molecular glues is that their dynamics go beyond a simple 1:1 binding model. Unlike traditional binding events, glues facilitate three-body interactions, where two proteins and the glue form a complex, and all components can interact with each other.
Because inducing cooperativity is so crucial in forming a strong binding complex, we prioritize cooperativity first in the search for new glues and then focus on raw or intrinsic binding affinity second. Since medicinal chemists have decades of experience behind them in optimizing binding affinity, it makes sense to select hits with high cooperativity as a starting point and improve the affinity later.
Q: Can you explain ‘cooperativity’ in a bit more detail?
PDV: Cooperativity is the key factor in determining how strongly a molecular glue promotes the interaction between two proteins. Simply put, more cooperativity generally means a stronger binding effect. It also plays an important role in determining selectivity; glues with high cooperativity will preferentially stabilize specific protein complexes, reducing off-target effects. So it’s all about cooperativity.
The level of cooperativity needed depends on the biological context. Some interactions are naturally weak, requiring a molecular glue to bring them into a relevant affinity range. Roughly speaking, shifting an interaction from 1% to 99% binding requires a 10,000-fold increase in affinity, meaning ideal cooperativity factors typically range from 100 to 10,000. On the other hand, if a weak interaction already exists but just needs a small boost, a cooperativity factor of around 40-fold can be sufficient to cause a cellular effect.
Q: How do you look for cooperativity?
PDV: To better understand and optimize cooperativity, we use thermodynamic models to simulate the expected titration behavior of molecular glues; essentially creating a “digital twin.” This helps in designing experiments, interpreting observed effects, and building intuition for how cooperativity and affinity interplay.
Cooperativity requires some intrinsic affinity for at least one of the targets to be observable, which also affects the concentration needed. These two requirements could function as a “double filter,” where hits must have both high cooperativity and sufficient initial affinity. Promising glue-like molecules may thus be overlooked using traditional discovery methods due to a lack of sensitivity in detecting these initially small effects.
Q: What could molecular glues mean for drug discovery research around more established targets?
PDV: Molecular glues are often discussed in the context of undruggable targets, but they also offer significant advantages for well-characterized targets. One major advantage is the potential for alternative mechanisms of action, which could help overcome resistance to traditional drugs. Additionally, because molecular glues interact with two proteins simultaneously, they may provide a way to fine-tune selectivity or create entirely new therapeutic opportunities.
Q: Why does your team hunt for molecular glues using fragments?
PDV: Fragments are an excellent starting point for discovering new molecular glues. Some of the most well-known glues, like lenalidomide (which targets CRBN/cereblon), is essentially a fragment with a molecular weight under 300 Da. Glues can be relatively simple, small molecules; we just require the right methodologies to identify them.
For example, a key approach to discovering new molecular glues is surface plasmon resonance (SPR). Since the SPR signal is proportional to the mass bound, it provides a clear advantage when screening for molecular glues. Because proteins are much heavier than small molecules, a glue that stabilizes a protein-protein complex will produce a significantly stronger SPR signal, making it a very powerful tool for detecting glue-mediated interactions.
To learn more about cooperativity-focused drug discovery for molecular glues, you can download a white paper detailing our methodology and approach.
Alternatively, get more information about Pim de Vink’s lecture at the 2nd SMR Molecular Glues Meeting on Friday 21st March 2025, Stevenage, UK, or check back for a recorded replay soon.
Pim de Vink is a Chemical Biologist currently working in the Assay Development and Screening Group at ZoBio (The Netherlands), which was acquired by Oncodesign Services in early 2024. After studying Chemistry at the University of Amsterdam, he pursued his Ph.D. at Eindhoven University of Technology under the supervision of Prof. Luc Brunsveld and Christian Ottmann, focusing on the principles of molecular glues. His current research interests include discovering new molecular glues and allosteric modulators, using integrated biophysical techniques, with Surface Plasmon Resonance (SPR) playing a significant role in his work.
The ZoBio team in Leiden, Netherlands, joined the Oncodesign Services group in early 2024, adding their extensive expertise and experience in tactical early discovery approaches to our existing late discovery and preclinical portfolio.
Want to discuss a molecular glue discovery project with our team? Contact us!
