What are the different types of drugs available for Molecular glue?

Introduction to Molecular Glues
Molecular glues are an emerging class of drugs that function by modulating protein–protein interactions (PPIs) to either destabilize, degrade, or sometimes stabilize key proteins that have historically been considered “undruggable.” Their mode of action is principally based on the ability of a small molecule to bind to one protein and thereby induce or stabilize its interaction with a second protein, often an E3 ubiquitin ligase, which leads to ubiquitination and subsequent proteasomal degradation of the target protein. This unique mechanism allows for the rewiring of intracellular pathways and intervention in diseases, particularly cancers, that are mediated by aberrant protein expression or dysregulated PPIs.

Definition and Mechanism of Action
At their core, molecular glues are typically low molecular weight compounds that promote the association between two distinct proteins. Unlike bifunctional degraders such as PROTACs, which contain two separate functional binding elements linked by a chemical spacer, molecular glues function as monovalent entities. They bind to one protein partner (often an E3 ubiquitin ligase or a regulatory protein) and alter its surface topology in a way that creates a new interface or enhances a latent interaction with a target protein. This process can lead either to the recruitment of the target protein for degradation or to modulation of its activity by enhancing protein complex stability. Over the years, several types of molecular glues have been found to trigger very distinct biochemical and cellular responses, ranging from protein degradation (thereby “removing” disease drivers) to stabilization of protein complexes that may restore beneficial signaling functions.

Historical Development and Significance
The concept of using small molecules to modulate protein–protein interactions dates back to the early discoveries of immunomodulatory agents. Early examples include drugs such as cyclosporine A and FK506 that were later understood to act as molecular glues by promoting the formation of protein complexes that inhibit calcineurin activity. Landmark cases include the identification of thalidomide and its derivatives (lenalidomide and pomalidomide) as molecular glues able to bind cereblon (a substrate receptor for a CUL4 ubiquitin ligase complex) and redirect it to target specific transcription factors for degradation—a discovery that revolutionized therapeutic approaches to multiple myeloma and other malignancies.
The significance of molecular glues derives from their ability not only to sabotage malignant signaling cascades by eliminating disease-causing proteins but also to transform “undruggable” targets into viable intervention points. With more than 80% of the human proteome considered undruggable by traditional inhibitor approaches due to a lack of well-defined binding pockets, molecular glues have opened up a vast new therapeutic landscape by relying on the modulation of areas involved in PPIs. Their discovery, initially driven by serendipity, has spurred intensive research to design rational strategies and high-throughput platforms—such as Rapid-Glue synthesis—to systematically explore and expand this drug modality.

Classification of Molecular Glue Drugs
The landscape of molecular glue drugs is broad and evolving rapidly as both serendipitous discoveries and rational design strategies contribute to a diverse set of compounds. The classification can be organized into three main types: small molecules, peptide-based glues, and other innovative approaches that sometimes combine elements of both or include novel mechanisms of action.

Small Molecules
Small-molecule glues constitute the majority of known molecular glue drugs. These compounds are generally characterized by a low molecular weight (typically under 500 Daltons) and are optimized for high bioavailability with favorable physicochemical properties. They act by binding to key proteins—often the E3 ubiquitin ligase—and modifying the protein surface such that a new interface is generated to recruit a target protein.
- Classical Examples:
Immunomodulatory imide drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide are prototypical examples of small-molecule molecular glues. These drugs were discovered serendipitously and later found to act by binding to cereblon, thereby redirecting its substrate specificity toward transcription factors such as Ikaros and Aiolos, leading to their degradation. Their success in clinical oncology for multiple myeloma underscores the therapeutic potential of small-molecule glues.
- Covalent Molecular Glues:
Recent advances have also highlighted the development of covalent molecular glues, where the small molecule forms either irreversible, reversible covalent, or time-dependent covalent bonds with the protein target. The introduction of an electrophilic group in these molecules enables them to react with nucleophilic residues (such as cysteine or lysine) on the protein surface, thereby stabilizing the protein–protein complex. For example, covalent molecular glue stabilizers have been explored through platforms that utilize aldehyde-based chemistries to induce covalent ligation after an initial non-covalent binding event.
- Rational Design Approaches:
With the evolution of high-throughput screening and computational methods such as deep generative modeling and structure-based drug design, small molecule glues are increasingly being designed with a more systematic approach. These innovations include fragment-based ligand discovery in combination with advanced docking methods, which help in identifying promising scaffolds that can serve as molecular glues with improved selectivity and potency.
Small molecules offer the advantages of easier chemical synthesis, oral bioavailability, and simpler pharmacokinetics, which are critical factors in drug development. The richness of the chemical space available for small molecules allows medicinal chemists to fine-tune their interactions with both E3 ligases and neosubstrate proteins, making them a versatile and widely pursued drug class.

Peptide-based Glues
Peptide-based molecular glues represent another innovative approach in the realm of induced proximity drugs. These compounds, derived from or modeled on peptide structures, utilize amino acid sequences to mediate interactions between proteins.
- Design Characteristics:
Peptide-based glues are typically derived from naturally occurring sequences or engineered to mimic binding motifs present in proteins. Their inherent ability to form secondary or tertiary structures allows them to effectively mimic protein–protein interface regions. Cyclization and backbone modifications are common strategies to improve their stability and resistance to proteolytic degradation in vivo.
- Advantages:
Due to their similarity to natural protein domains, peptide-based glues can offer high specificity and selectivity. They provide an excellent starting point for modulating PPIs where the interactions are finely tuned by intrinsic amino acid properties. Moreover, the possibility of incorporating D-amino acids or cyclization strategies allows these peptides to exhibit enhanced pharmacokinetics and stability compared to linear peptides.
- Therapeutic Potential:
Peptide glues have been explored for applications not only in targeted protein degradation but also in the stabilization of transiently interacting protein complexes. For example, peptide-based glues may be designed to activate or inhibit specific signaling cascades by ensuring that underexpressed or misfolded proteins form functional complexes. Although their development still faces challenges related to cellular permeability and metabolic stability, recent advances in conjugation techniques and nanoparticle delivery are promising.
Peptide-based glues can be tailored for both intracellular and extracellular targets, offering a complementary approach to traditional small-molecule glues. Their modularity and the possibility of rational design based on structural motifs provide a robust platform for therapeutic innovation.

Other Innovative Approaches
Beyond the classic differentiation between small molecules and peptides, other innovative approaches blend or extend the concept of molecular glues.
- Hybrid and Conjugate Approaches:
Some strategies involve the conjugation of a small-molecule glue with other modalities such as antibodies, aptamers, or other targeting ligands to enhance tissue-specific delivery and binding affinity. These hybrid molecules aim to combine the advantages of the small-molecule’s bioavailability with the high specificity of larger biomolecules. Conjugated forms, such as the tissue-binding small molecule conjugates with chemotherapeutic agents, have been explored to improve the efficacy and selectivity of drug delivery.
- Covalent–Noncovalent Dual Mechanisms:
As mentioned in the discussion on covalent molecular glues, a subset of these compounds utilizes a two-step mechanism where an initial non-covalent complex formation is followed by a slower covalent bonding event. This dual mechanism enhances the stability of the ternary complex formed between the E3 ligase, the glue, and the target protein, thereby ensuring sustained drug activity.
- Platforms Leveraging Combinatorial Synthesis:
Platforms such as Rapid-Glue have been developed to synthesize libraries of putative molecular glues in a high-throughput manner. These methods combine miniaturized synthesis techniques with direct cellular screening, which not only speeds up the process of identifying active molecules but also allows for the exploration of more diverse chemical spaces.
- Machine Learning and Computational Innovations:
With the advent of de novo drug design and deep generative modeling, computational approaches are increasingly being integrated into the discovery of molecular glues. Machine learning models, trained on existing datasets of active glues, are being used to predict new chemical scaffolds capable of templating PPIs. These approaches promise to move the discovery process from being serendipitous to truly rational, expanding the possibilities for discovering unconventional glues that might have been overlooked by conventional screening techniques.
Other innovative approaches are being designed with the goal of not only inducing protein degradation (via E3 ligases) but also stabilizing beneficial protein–protein interactions to restore disrupted cellular signaling. This dual functionality further underscores the versatility and potential of molecular glues as a drug modality.

Applications and Examples
The application of molecular glues spans a wide array of therapeutic areas, reflecting their potential to modulate proteins that drive different pathologies. Their utility has been demonstrated both in clinical and preclinical studies, with several approved drugs serving as case studies.

Therapeutic Areas
Molecular glues are particularly promising in the field of oncology, where the ability to target transcription factors and oncogenic proteins that are otherwise considered undruggable is of paramount importance.
- Oncology:
One of the most successful applications of molecular glues is in the treatment of multiple myeloma and other hematologic malignancies. For instance, thalidomide and its derivatives (lenalidomide and pomalidomide) work by reprogramming the E3 ligase cereblon to degrade key transcription factors involved in tumor survival. Their clinical performance, coupled with their favorable pharmacokinetic profiles, has spurred further investigation into molecular glue degraders as anti-cancer agents. Novel platforms are exploring additional targets in cancer where conventional inhibitors have failed.
- Immunology:
Beyond oncology, molecular glues have emerged as tools for immune modulation. By targeting proteins that regulate immune cell activation and cytokine production, these glues can be harnessed to treat autoimmune conditions and inflammatory disorders. For example, recent news reports have highlighted the development of molecules aimed at modulating key signaling proteins in T- and B-cell cascades via molecular glue mechanisms.
- Neurodegeneration:
In neurodegenerative diseases, restoring protein homeostasis represents a key therapeutic strategy. Molecular glues have the potential to direct the degradation of misfolded or aggregated proteins that contribute to the progression of diseases such as Alzheimer’s and Parkinson’s. Additionally, by stabilizing specific beneficial protein complexes, these glues might also promote neuroprotective pathways.
- Other Areas:
Research is also ongoing into the use of molecular glues in rare diseases, metabolic dysfunctions, and even infectious diseases, where targeted protein degradation could disrupt the life cycle of pathogens or modulate host responses.
These examples underscore the versatility of molecular glues as a class of therapeutic agents capable of addressing multiple disease indications by precisely modulating protein–protein interactions.

Case Studies of Approved Drugs
Some of the best-known and most clinically successful molecular glue drugs have set the benchmark for the field:
- Thalidomide Derivatives:
Thalidomide, despite its infamous past, and its derivatives lenalidomide and pomalidomide, are paradigmatic examples of small-molecule molecular glues. They operate via binding to cereblon, leading to the recruitment and subsequent degradation of distinct transcription factors. Their clinical approval for multiple myeloma and other hematologic malignancies is a testament to the successful translation of molecular glue mechanisms into safe and effective therapies.
- Emerging Candidates in Clinical Trials:
Recent news has highlighted experimental molecules such as mezigdomide, which is in clinical trials for multiple myeloma and is another example of a small-molecule molecular glue targeting disease-relevant proteins. Furthermore, several companies are advancing molecular glues that target critical proteins in oncological and immune-mediated conditions, demonstrating both the breadth of the technology and outcomes in early-phase clinical trials.
- Case Studies Highlighting the Diversity:
In addition to conventional degradation targets, case studies have also revealed molecular glues that function by stabilizing protein complexes. For example, certain compounds identified through covalent molecular glue screening have shown great promise in stabilizing complexes that sequester and inactivate disease-mediating proteins. This dual functionality—both degradation and stabilization—illustrates the adaptability of molecular glues to diverse therapeutic strategies.
These case studies, derived from both clinical use and ongoing research, illustrate how molecular glue drugs have evolved from serendipitous discoveries to highly engineered therapeutics that are reshaping modern drug discovery.

Challenges and Future Directions
While molecular glues have opened exciting new vistas in drug design, several challenges remain. The future of this modality depends on overcoming these hurdles through continued interdisciplinary research and innovation.

Current Challenges in Development
There are a number of technical, biological, and regulatory challenges that continue to hamper the full realization of molecular glue drugs’ potential:
- Discovery Process Reliant on Serendipity:
One of the intrinsic challenges in molecular glue discovery is the largely serendipitous nature of initial hits. Many molecular glues have been discovered by chance during transitions in high-throughput screening campaigns. Although this has yielded several clinically successful compounds, the lack of a systematic, predictive approach makes it difficult to explore the full chemical space associated with induced protein–protein interactions.
- Design and Optimization Complexity:
The mechanistic underpinnings of molecular glues involve a mix of non-covalent and covalent binding interactions that are often nonadditive and highly cooperative. This complexity poses challenges in rational design. Traditional computational techniques such as docking have limited capabilities in predicting and accurately modeling these multi-step binding events, which necessitates advanced biophysical tools like native mass spectrometry to unravel the kinetics of complex assembly.
- Pharmacokinetic and Pharmacodynamic Considerations:
Despite their small size and favorable physicochemical properties, ensuring that molecular glues deliver sufficient target occupancy and maintain stable ternary complexes in the biological milieu is a major challenge. Issues such as off-target effects, rapid metabolism, and the potential for undesirable immune responses are under continuous investigation.
- Limited Ligase and Substrate Repertoire:
In many cases, the majority of molecular glue drugs discovered to date tend to leverage a select few E3 ligases (for example, cereblon and VHL). Broadening the range of ligases utilized in targeted protein degradation could substantially expand the therapeutic scope of molecular glues. However, identifying and validating alternative ligases remain a significant hurdle.
- Screening and Assay Development:
The identification of effective molecular glues requires the development of robust assays that can accurately detect induced PPIs and subsequent biological effects. The sensitivity of these assays must be sufficient to capture both transient interactions as well as the cumulative effect of slow covalent binding events, which calls for innovative experimental designs and integrated computational–experimental workflows.

Future Research and Potential Innovations
The future of molecular glue drugs lies in addressing the aforementioned challenges by leveraging advances in chemical biology, computational methods, and high-throughput screening technologies:
- Rational Design and Machine Learning:
The integration of deep generative models, de novo drug design algorithms, and machine learning is already beginning to reshape how molecular glues are discovered. By training models on existing datasets and employing structure-based design, researchers hope to gradually shift from serendipitous discoveries to rational, predictive strategies that can systematically explore vast chemical spaces for candidates with optimal binding characteristics.
- Expansion of Chemical Libraries:
Platforms such as Rapid-Glue enable the rapid synthesis of diverse libraries of potential molecular glues using miniaturized chemistry and direct biological screening. This approach not only accelerates the identification of active compounds but also facilitates a more systematic mapping of structure–activity relationships for molecular glues. The increased library diversity holds promise for discovering novel molecules targeting previously unexplored protein interactions.
- Adoption of Advanced Biophysical Techniques:
Techniques such as native mass spectrometry, time-dependent fluorescence anisotropy assays, and real-time kinetic analyses are paving the way for a better understanding of the sequential binding events underlying molecular glue activity. A more in-depth mechanistic understanding will guide the rational optimization of these compounds for improved selectivity and sustained target engagement.
- Broadening the Target Space:
Expanding the range of protein targets—beyond those traditionally modulated by cereblon and VHL—is another key research direction. By exploring alternative E3 ligases and targeting novel protein–protein interfaces, it may be possible to develop molecular glue strategies for a much wider spectrum of diseases, including those related to neurodegeneration, infectious diseases, and metabolic disorders.
- Hybrid and Conjugate Strategies:
Future therapies may involve hybrid molecules that combine the favorable properties of small molecules and peptides, or that integrate molecular glues with drug delivery platforms such as nanoparticles and antibody conjugates. Such combination approaches have the potential to improve tissue specificity, minimize off-target effects, and enhance overall therapeutic efficacy.
- Regulatory and Translational Considerations:
In parallel with scientific and technological advances, regulatory pathways need to evolve to accommodate the unique characteristics of molecular glue drugs. Establishing robust proof-of-concept studies, detailed mechanistic insights, and precise biomarkers will be crucial for guiding clinical development and ensuring patient safety.
- Interdisciplinary Collaborations:
The future success of molecular glue drugs will greatly benefit from sustained collaboration among computational chemists, structural biologists, medicinal chemists, and clinicians. By integrating insights from different disciplines, the field can transition towards a more systematic and holistic approach to drug discovery, ultimately leading to the translation of promising molecular glue candidates from the laboratory to the clinic.

Conclusion
In summary, the different types of drugs available for molecular glue can be categorized into three major groups: small molecules, peptide-based glues, and other innovative hybrid or conjugate approaches. Small molecules remain the most extensively studied and clinically validated class, with thalidomide derivatives serving as prime examples of their success in oncology and immunotherapy. Peptide-based glues offer the advantage of high specificity and mimic natural binding motifs, though challenges persist in terms of stability and delivery. Other innovative strategies, including covalent–noncovalent dual mechanisms and hybrid platforms, are expanding the possibilities for targeting an even broader array of disease-relevant proteins.

The therapeutic applications of molecular glues span oncology, immunology, neurodegeneration, and beyond, highlighting their potential to tackle diseases with previously “undruggable” targets. Case studies from clinical practice—most notably the thalidomide derivative family—demonstrate significant clinical benefits and validate the approach. However, challenges related to serendipitous discovery, complexity of mechanism, limited screening technologies, and regulatory hurdles remain formidable.

Future research is oriented toward rational design using machine learning, expanding chemical libraries using innovative synthesis platforms, and integrating advanced biophysical techniques to unravel the kinetics and thermodynamics of glue-induced protein complexes. Interdisciplinary collaborations and the expansion of target spaces will be pivotal for overcoming current limitations and translating molecular glues into transformative therapies.

This comprehensive overview—from the basic definition and evolution of molecular glues, through their classification and practical applications, to the challenges and future directions—illustrates that molecular glue drugs represent a unique and promising therapeutic modality. Their ability to modulate protein–protein interactions at a fundamental level opens a wide arc of possibilities for the treatment of complex diseases. Continued innovation in design, screening, and mechanistic understanding will undoubtedly accelerate their journey from promising leads to widely used clinical therapeutics.