How Molecular Glue is Transforming Drug Discovery

This class of small molecules is reshaping the principles of drug discovery by shifting the focus from traditional occupancy-driven modulation of protein activity to strategies that enhance or induce protein-protein interactions (PPIs). In a promising event-driven modality, these molecules can exploit the body’s natural protein degradation pathways to selectively degrade disease-causing proteins (targeted protein degradation, TPD), but driving interactions can also lead to functional changes in protein activity directly. 

Hence, the value of molecular glues lies in their ability to overcome the limitations of traditional drug development, offering the potential to target proteins that were once deemed impossible to target. 

The potential of such drugs is tremendous — it is estimated that only 10% of the coding genome is druggable by traditional small molecule inhibitors. The remaining 90% includes proteins involved in protein complexes or in DNA/RNA binding, which due to their function often have flat or protruding surfaces adapted to interact with other proteins or nucleic acids but not small molecules. Many proteins, such as transcription factors and scaffolding proteins tend to be intrinsically disordered, having regions that fold only in the presence of protein co-factors and are therefore normally unavailable for the binding of small molecules.

The term molecular glue refers to a type of small molecule that affect PPIs, either by inducing de novo protein-protein interactions, or by stabilizing already existing interactions, resulting in stable ternary complexes. 

Most molecular glue approaches address the interaction between a target protein and an E3 ubiquitin ligase – thereby inducing the selective degradation of the target protein via the proteasomal pathway. This targeted protein degradation (TPD) approach circumvents many limitations of traditional therapeutics and offers a powerful tool for addressing diseases, simply by removing disease-causing proteins. Molecular glues differ from other TPD modalities, such as PROTACs (Proteolysis Targeting Chimeras), by being monovalent and structurally simpler, yet equally potent in facilitating protein-protein interactions.

The ability to direct protein degradation has far-reaching implications for drug development, especially for targeting non-druggable proteins like transcription factors and scaffolding proteins that are traditionally difficult to engage with small molecule inhibitors.

Key molecular glue properties include high specificity, stability, cell permeability, and the capacity to induce novel protein-protein interactions that do not naturally occur, or to strengthen naturally occurring interactions.

Molecular glues are in general characterized by their small molecular weight and monovalent binding nature. Unlike bifunctional molecules like PROTACs, which consist of two linked ligands targeting a protein and an E3 ligase, respectively, molecular glues bind a single site and induce a new protein interface that promotes the formation of a ternary complex.

The mode of action of molecular glues typically involves altering the surface properties of one protein (often an E3 ligase), thereby enhancing its affinity for a secondary protein (the target). 

Similarly, molecular glues can complement missense mutations, providing for example ‘‘molecular prosthetics’’ as novel modalities in medicine, such as those seen when the disease-causing W580S missense mutation in MALT1 can be ameliorated with the MALT1 binder MLT748. W580 stabilizes an intramolecular interaction, and MLT748 can bind in the pocket created in the W580S mutant and mediate the domain-domain interaction that is crucial for MALT1 activity (Quancard et al., 2019). 

Clinical examples like the use of lenalidomide and pomalidomide show how molecular glues work in the context of cancer. These drugs interact with the E3 ligase cereblon, facilitating the ubiquitination and subsequent degradation of the transcription factors IKZF1 and IKZF3. In this case, lenalidomide and pomalidomide mimic a PTM that marks proteins for cellular degradation (the C-terminal cyclic imide ‘‘degron,’’). This degradation is critical for the treatment of multiple myeloma, underscoring the therapeutic potential of molecular glues in oncology.

The mechanism of molecular glue-induced protein degradation operates through the ubiquitin-proteasome system (UPS), a crucial cellular pathway for maintaining protein homeostasis. Once a target protein is tagged with polyubiquitin by an E3 ligase, it is recognized and degraded by the 26S proteasome. Molecular glues exploit this pathway by reprogramming the substrate specificity of E3 ligases—turning them into tools for selective protein clearance.

This approach allows for a more complete and irreversible silencing of disease-associated proteins compared to reversible inhibition. Moreover, molecular glue-induced degradation has been shown to produce fewer off-target effects, and is associated with reduced drug resistance, making it a promising strategy in precision medicine. In some cases, this degradation may result in the activation of other cellular pathways, offering the potential for broader therapeutic benefits.

Cancer treatment has been one of the most prominent areas of molecular glue application. As mentioned above, thalidomide derivatives, for instance, have demonstrated clinical efficacy in multiple myeloma by targeting transcription factors essential for cancer cell survival. The degradation of IKZF1 and IKZF3 by lenalidomide and pomalidomide not only highlights the clinical relevance of molecular glue but also underscores its potential for targeting proteins traditionally considered undruggable (Lu et al., 2014).

The emerging generation of molecular glues aims to address a wider array of cancer types. Notably, the targeting of oncogenic proteins like BCL6 and STAT3, which are involved in the regulation of immune responses and tumor progression, is being actively explored. For example, studies on BCL6 suggest that molecular glues can cause it to multimerize, resulting in its degradation. (Slabicki, et al., (2020).

Beyond oncology, molecular glue has shown promise in the treatment of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease. 

For example, tafamidis is used to treat both senile and hereditary transthyretin (TTR) amyloidosis, which is caused by the deposition of transthyretin polymers in neuronal and cardiac tissues. It works by stabilizing TTR tetramers via PPI interface binding, thereby precluding monomerization, polymerization, amyloidosis, and subsequent disease. Tafamidis is an excellent example of how stabilizing one endogenous PPI state over another can treat pathology, a model with utility in other aggregation and fibril-related diseases.

In a broader sense, by promoting the degradation of pathogenic proteins like tau, alpha-synuclein, and huntingtin, molecular glues offer a novel therapeutic avenue that addresses the root cause of neurodegeneration rather than merely alleviating symptoms. 

Similarly, in antiviral research, molecular glues are being explored for their ability to target viral proteins or host factors essential for viral replication. Emerging studies suggest that reprogramming E3 ligases to degrade specific viral components could offer a new strategy for combating resistant strains of HIV, hepatitis viruses, and even coronaviruses (Zhong et al., 2024).

The integration of molecular glue into structure-guided drug design is revolutionizing medicinal chemistry. Advances in cryo-electron microscopy (cryo-EM), X-ray crystallography, and computational modeling are facilitating the rational design of glues that optimize the shape, charge, and hydrophobic interactions required for effective protein-protein binding.
Machine learning algorithms and AI-driven platforms are also playing a pivotal role in predicting glue-like activity and guiding compound optimization. These tools allow the prediction of novel interactions, the identification of binding hotspots, and the tailoring of molecular properties to enhance selectivity and pharmacokinetics. The result is a more efficient drug development pipeline and an expanding repertoire of molecular glues with high therapeutic potential.
Emerging trends also show the combination of molecular glue strategies with other cutting-edge technologies like CRISPR-Cas9 to create more precise and effective therapeutic interventions. The potential for precision editing of E3 ligases, combined with the power of molecular glues, could lead to more personalized treatments with minimized off-target effects.

Despite their immense promise, molecular glues face several challenges. One major limitation is the current lack of high-throughput screening platforms specifically tailored to detect novel interactions. Here, recent developments in screening technologies, such as DEL based screening for molecular glues can become of importance. Additionally, for TPD, increasing the knowledge on suitable E3 ligases with favourable tissue- or cell-type specific expression will be of utmost importance for expanding the molecular toolbox available for the development of novel therapies.

Emerging biotechnologies such as targeted protein stabilization and autophagy-based degraders (AUTACs and ATTECs) may also be integrated with molecular glue strategies to broaden their therapeutic scope.

Currently, there is a primary focus on the use of molecular glues for TPD, but it is well known, that protein–protein interactions are vital for the regulation of virtually all cellular processes, from signalling to DNA replication, and that aberrant PPIs are causing several diseases. The concept of protein degradation induced by novel protein-protein interactions has inspired a broader field of induced-proximity modulators, and recently several proximity-driven approaches have been reported, such as deubiquitinase-targeting chimeras, lysosome-targeting chimeras, phosphorylation-inducing small molecules, tricomplex inhibitors of kRAS, and more. Thus, a new era of targeting disease-causing mechanisms and proteins previously regarded as undruggable may very well arise as the methods for discovery of molecular glues and other proximity-driven pharmaceuticals are refined and more widely used.

When comparing molecular glues to traditional degraders like PROTACs, several distinct advantages and trade-offs emerge. 

PROTACs offer a modular design, with high flexibility in targeting diverse protein domains. Their bivalent nature also simplifies the discovery phase in many cases, albeit at the cost of increased synthetic complexity and larger molecular size. 

From a drug discovery perspective DELs are in general well suited for the discovery of heterobifunctional molecules (PROTAC like molecules) as the discovery of binders to POI and E3 ligase is well established. In addition, the DNA attachment site on the small molecule indicates a potential molecular position for placing the linker between binders.

Molecular glues are smaller, simpler, and often more stable, which improves cell permeability and oral bioavailability. They do not require linker optimization and, once discovered, provide a shorter route from discovery to pharmaceutically usable molecules. 

As mentioned above, the drawback is that the discovery of molecular glues is not straight-forward, although some strategies have been pursued, hereunder DEL screening approaches. 

In practice, both approaches are complementary. The integration of both strategies within the same therapeutic pipeline could ultimately maximize the efficiency and range of targeted protein degradation therapies.

References and further reading

• Békés, M., et al., (2022). PROTAC targeted protein degraders: The past is prologue. Nature Reviews Drug Discovery, 21, 181. https://doi.org/10.1038/s41573-021-00371-6
• Krönke, J., et al. (2014). Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science, 343, 30. https://doi.org/10.1126/science.1244851
• Lamb, Y.N., Deeks, E.D. (2019). Tafamidis: A Review in Transthyretin Amyloidosis with Polyneuropathy. Drugs 79, 863–874. https://doi.org/10.1007/s40265-019-01129-6
• Liu, J. ∙ Farmer, Jr., J.D. ∙ Lane, W.S. (1991) Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes Cell, 66, 807. https://doi.org/10.1016/0092-8674(91)90124-h
• Lu, G., et al. (2014). The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science, 343, 305. https://doi.org/10.1126/science.1244917
• Mayor-Ruiz, C., et al. (2020). Rational discovery of molecular glue degraders via scalable chemical profiling. Nature Chemical Biology, 16, 1199. https://doi.org/10.1038/s41589-020-0594-x 
• Quancard, J. et al., (2019). An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient. Nature Chemical Biology 15, 304. https://doi.org/10.1038/ s41589-018-0222-1
• Schreiber, S.L (2024). Molecular glues and bifunctional compounds: Therapeutic modalities based on induced proximity. Cell Chemical Biology 31, 1050. https://doi.org/10.1016/j.chembiol.2024.05.004
• Slabicki, M., et al (2020). Small-molecule-induced polymerization triggers degradation of BCL6. Nature 588, 164. https://doi.org/10.1038/s41586-020-2925-1
• Simonetta KR., et al (2019). Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction. Nature Communications 10, 1402. https://doi.org/10.1038/s41467-019-09358-9.
• Tomlinsson, A.C.A. et al., (2025). The “three body solution”: Structural insights into molecular glues. Current Opinion in Structural Biology 91, 103007. https://doi.org/10.1016/j.sbi.2025.103007
• Yoon H., et al. (2024). Induced protein degradation for therapeutics: past, present, and future J Clinical Investigation. 134: e175265. https://doi.org/10.1172/JCI175265
• Zhong G. et al., (2024) Targeted protein degradation: advances in drug discovery and clinical practice. Signal Transduct Target Therapy 9, 308. https://doi.org/10.1038/s41392-024-02004-x