Molecular glue

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Auxin's mechanism of action, which led to the popularization of the term 'molecular glue.' Ub = ubiquitin; R = Rbx1; E2 = E2 ubiquitin-conjugating enzyme. Auxin's mechanism of action, which led to the popularization of the term 'molecular glue.' Ub = ubiquitin; R = Rbx1; E2 = E2 ubiquitin-conjugating enzyme.png
Auxin's mechanism of action, which led to the popularization of the term 'molecular glue.' Ub = ubiquitin; R = Rbx1; E2 = E2 ubiquitin-conjugating enzyme.

A molecular glue is a type of small molecule that modulates a protein-protein interaction in cells. These compounds can induce new interactions between proteins (type I) or enhance existing ones (type II), offering an alternative approach to traditional drug discovery. Molecular glues have shown potential in targeting proteins previously considered "undruggable" by conventional methods. They work through various mechanisms, such as promoting protein degradation or inhibiting protein function, and are being studied for potential use in treating cancer, neurodegenerative disorders, and other diseases.

Contents

Unlike PROTACs, which are rationally designed heterobifunctional molecules that contain two covalently linked ligands that bind respectively to a target protein and an E3 ligase, molecular glues are small, monofunctional compounds typically discovered serendipitously through screening or chance observations.

Mechanism of action

Molecular glue compounds are typically small molecules that facilitate interactions between proteins by stabilizing or inducing protein–protein interactions (PPIs). These compounds often bind to specific binding sites on a target protein and alter its surface conformation, promoting interactions with other proteins that would not normally associate. By reshaping protein surfaces, molecular glues can stabilize protein complexes, reducing their tendency to dissociate, and thus modulate essential cellular functions, many of which rely on dynamic protein assemblies. Through this mechanism, molecular glues can alter the function, localization, or stability of target proteins, offering valuable applications in both therapeutic and research contexts. [2]

Unlike PROTACs, which are bifunctional and physically tether the target to an E3 ubiquitin ligase, molecular glues induce or enhance PPIs between the ligase and the substrate by binding at existing or latent interaction surfaces. [3] This mechanism allows for selective targeting of proteins, including those previously considered "undruggable."

A notable example involves small molecules that promote the interaction between the oncogenic transcription factor β-Catenin and the E3 ligase SCFβ-TrCP. These molecules function as molecular glues by enhancing the native PPI interface, resulting in increased ubiquitylation and subsequent degradation of mutant β-Catenin both in vitro and in cellular models. [3] Unlike PROTACs, which require two separate binding moieties, these monovalent molecules insert directly into the PPI interface, simultaneously optimizing contacts with both substrate and ligase within a single chemical entity. [3]

Molecular glues are especially advantageous for degrading non-ligandable targets, as they exploit naturally complementary protein surfaces to induce degradation without requiring high-affinity ligands for the target protein. [3] Although many molecular glues have historically been discovered serendipitously and characterized retrospectively, newer approaches now aim to identify them prospectively through systematic chemical profiling. [4]

For example, the compound CR8 was identified through correlation analysis as a molecular glue that promotes ubiquitination and degradation of specific targets via a top-down screening approach. [5] This highlights the broader potential of small molecules, beyond PROTACs, in targeted protein degradation strategies. [5]

There is also growing evidence that molecular glues can stabilize interactions beyond protein–protein pairs, including protein–RNA [6] and protein–lipid complexes. [7]

Functional types

Molecular glues are categorized into functional types based on their mechanisms of modulating protein-protein interactions (PPIs): stabilization of non-native (type I) or native (type II) protein-protein interactions.

Type I (non-native)

Type I molecular glues induce non-native protein-protein interactions that physically block, or "shield," a protein’s normal endogenous activity. Rather than promoting protein degradation, these compounds typically stabilize inactive conformations [2] or mask functional regions of the target protein, thereby preventing it from participating in its usual biological processes. This can include blocking active sites, disrupting ligand binding, or interfering with native protein–protein interactions. [8] [9]

One example is the immunosuppressant rapamycin, which forms a ternary complex with FKBP12 and the kinase mTOR, resulting in inhibition of mTOR activity. Another is cyclosporin A, which bridges cyclophilin A and calcineurin, leading to inhibition of calcineurin’s phosphatase function. These cases illustrate how Type I molecular glues can modulate protein function by enforcing artificial protein interactions that hinder normal activity.

Type II (native)

Type II molecular glues stabilize endogenous protein-protein interactions by altering protein conformation or dynamics. They can either inhibit or enhance activity by locking proteins into specific states. One example is lenalidomide (an immunomodulatory drug), which binds cereblon (CRBN) and reprograms it to degrade transcription factors like IKZF1/IKZF3 in multiple myeloma. [9] Other examples include tafamidis that stabilizes transthyretin (TTR) tetramers to prevent amyloid fibril formation in neurodegenerative diseases and paclitaxel that stabilizes microtubule polymers, blocking disassembly and inhibiting cancer cell division [8]

Interaction mechanisms

Molecular glues employ two primary mechanisms to modulate protein-protein interactions (PPIs): allosteric regulation and direct bridging. [9] Allosteric mechanisms dominate therapeutic applications of molecular glues because of their versatility in targeting diverse proteins and pathways. [10]

Allosteric regulation

In allosteric regulation, molecular glues bind to one protein, inducing conformational changes that create or stabilize novel interaction surfaces, enabling the recruitment of a second protein. [11] For example, lenalidomide binds to the E3 ligase cereblon (CRBN), remodeling its surface to recruit neo-substrates such as IKZF1/IKZF3 for ubiquitination and subsequent degradation. [12] Similarly, CC-885 binds CRBN and induces the degradation of GSPT1 by stabilizing a ternary complex between CRBN, GSPT1, and the molecular glue. [13]

Direct bridging

In contrast, direct bridging involves the glue physically linking two proteins at their interface. For instance, rapamycin bridges FKBP12 and mTOR by binding to both proteins simultaneously, forming a ternary complex that inhibits mTOR’s kinase activity. [14] While direct bridging is observed in some cases, allosteric modulation is far more common in molecular glues due to its ability to exploit dynamic protein surfaces and induce novel interactions without requiring pre-existing binding pockets. [10]

Applications

The ability of molecular glues to selectively degrade disease-relevant proteins has significant implications for drug discovery, particularly in the context of "undruggable" targets. Their monovalent nature and reliance on endogenous PPIs make them especially appealing for therapeutic development.

Compared to traditional small molecule drugs, molecular glues offer several advantages, including lower molecular weight, improved cell permeability, and favorable oral bioavailability. These properties align with the "Five Rules for Drugs" and may enable more efficient delivery and distribution in vivo. [3]

In contrast, PROTACs—though similarly used for targeted protein degradation—often face challenges such as high molecular weight, reduced cell permeability, and poor pharmacokinetic profiles, which can hinder their clinical development. [3]

Several therapeutic molecular glues have been developed to target proteins involved in cancer and other diseases. For instance, small molecule degraders of BCL6 and Cyclin K exploit both ligand-binding and PPI surfaces to drive the formation of ternary complexes with E3 ligases. [15] These compounds, typically under 500 Da, promote tight binding between ligase and neosubstrate in the presence of the glue and demonstrate high potency in cellular models. [15]

As research continues to uncover new targets and refine discovery approaches, molecular glues are expected to play an increasingly important role in precision medicine and targeted degradation therapies.

Cancer therapy

Molecular glue compounds have demonstrated significant potential in cancer treatment by influencing protein-protein interactions (PPIs) and subsequently modulating pathways promoting cancer growth. These compounds act as targeted protein degraders, contributing to the development of innovative cancer therapies. [16] The high efficacy of small-molecule molecular glue compounds in cancer treatment is notable, as they can interact with and control multiple key protein targets involved in cancer etiology. [16] This approach, with its wider range of action and ability to target "undruggable" proteins, holds promise for overcoming drug resistance and changing the landscape of drug development in cancer therapy. [16]

Neurodegenerative diseases

Molecular glue compounds are being explored for their potential in influencing protein interactions associated with neurodegenerative diseases such as Alzheimer's and Parkinson's. By modulating these interactions, researchers aim to develop treatments that could slow or prevent the progression of these diseases. [16] Additionally, the versatility of small-molecule molecular glue compounds in targeting various proteins implicated in disease mechanisms provides a valuable avenue for unraveling the complexities of neurodegenerative disorders. [16]

Antiviral research

Molecular glue compounds, particularly those involved in targeted protein degradation (TPD), offer a novel strategy for inhibiting viral protein interactions and combating viral infections. [17] Unlike traditional direct-acting antivirals (DAAs), TPD-based molecules exert their pharmacological activity through event-driven mechanisms, inducing target degradation. This unique approach can lead to prolonged pharmacodynamic efficacy with lower pharmacokinetic exposure, potentially reducing toxicity and the risk of antiviral resistance. [17] The protein-protein interactions induced by TPD molecules may also enhance selectivity, making them a promising avenue for antiviral research. [17]

Chemical biology

Molecular glue serves as a valuable tool in chemical biology, enabling scientists to manipulate and understand protein functions and interactions in a controlled manner. [16] The emergence of targeted protein degradation as a modality in drug discovery has further expanded the applications of molecular glue in chemical biology. [17] The ability of small-molecule molecular glue compounds to induce iterative cycles of target degradation provides researchers with a powerful method for studying protein-protein interactions and opens avenues for drug development in various human diseases. [17]

Examples

Type I

Induce non-native PPIs to block or inhibit target activity without degradation:

Type II

Redirect or stabilize PPIs to induce target degradation.

CRBN-Based Degraders:

History

The concept of "molecular glue" originated in the late 20th century, with immunosuppressants like cyclosporine A (CsA) and FK506 identified as pioneering examples. [46] CsA, discovered in 1971 during routine screening for antifungal antibiotics, exhibited immunosuppressive properties by inhibiting the peptidyl–prolyl isomerase activity of cyclophilin, ultimately preventing organ transplant rejections. [47] By 1979, CsA was used clinically, and FK506 (tacrolimus), discovered in 1987 by Fujisawa, emerged as a more potent immunosuppressant. [47] The ensuing 4-year race to understand CsA and FK506's mechanisms led to the identification of FKBP12 as a common binding partner, marking the birth of the "molecular glue" concept. [47] The term molecular glue found its way into publications in 1992, highlighting the selective gluing of specific proteins by antigenic peptides, akin to immunosuppressants acting as docking assemblies. [47] The term, however, remained esoteric and hidden from keyword searches.

In the early 1990s, researchers delved into understanding the role of proximity in biological processes. [47] The creation of synthetic "chemical inducers of proximity" (CIPs), such as FK1012, opened the door to more complex molecular glues. [47] Rimiducid, a purposefully synthesized molecular glue, demonstrated its effectiveness in eliminating graft-versus-host disease by inducing dimerization of death-receptor fusion targets. [47]

The exploration of molecular glues took a significant turn in 1996 with the discovery that discodermolide stabilized the association of alpha and beta tubulin monomers, functioning as a "molecular clamp" rather than inducing neo-associations. [47] In 2000, the revelation that a synthetic compound, synstab-A, could induce associations of native proteins marked a shift towards the discovery of non-natural molecular glues. [47]

In 2001, Kathleen Sakamoto, Craig M. Crews and Raymond J. Deshaies raised the concept of PROTACs, which consist of a heterobifunctional molecule with a ligand of an E3 ubiquitin ligase linked to a ligand of a target protein. [48] PROTACs are synthetic CIPs acting as protein degraders.

In 2007, the term “molecular glue” became popularized after it was independently coined by Ning Zheng to describe the mechanism of action of auxin, a class of plant hormones regulating many aspects of plant growth and development. [1] By promoting the interaction between a plant E3 ubiquitin ligase, TIR1, and its substrate proteins, auxin induces the degradation of a family of transcriptional repressors. [49] Auxin is chemically known as indole-3-acetic acid and has a molecular weight of 175 dalton. Unlike PROTACs and immunosupressants such as CsA and FK506, auxin is a chemically simple and monovalent compound with drug-like properties obeying Lipinski’s rule of five. With no detectable affinity to the polyubiquitination substrate proteins of TIR1, auxin leverages the intrinsic weak affinity between the E3 ligase and its substrate proteins to enable stable protein complex formation. The same mechanism of action is shared by jasmonate, another plant hormone involved in wound and stress responses. [50] The term “molecular glue” has since been used, particularly in the context of targeted protein degradation, to specifically describe monovalent compounds with drug-like properties capable of promoting productive protein-protein interactions, instead of CIPs in general.

In 2013, the mechanism of thalidomide analogs as molecular glue degraders had been revealed. [46] Notably, thalidomide, discovered as a CRBN ligand in 2010, and lenalidomide enhance the binding of CK1α to the E3 ubiquitin ligase, solidifying their role as molecular glues. [46] [47] Subsequently, indisulam was identified as a molecular glue capable of degrading RBM39 by targeting DCAF15 in 2017. [46] These compounds are considered molecular glues because of their monovalency and chemical simplicity, which are consistent with the definition proposed by Shiyun Cao and Ning Zheng. [51] Analogous to auxin, these compounds are distinct from PROTACs, displaying no detectable affinity to the substrate proteins of the E3 ubiquitin ligases.

The year 2020 saw the discovery of autophagic molecular degraders and the identification of BI-3802 as a molecular glue inducing the polymerization and degradation of BCL6. [46] Additionally, chemogenomic screening revealed structurally diverse molecular glue degraders targeting cyclin K. [46] The discovery that manumycin polyketides acted as molecular glues, fostering interactions between UBR7 and P53, further expanded the understanding of molecular glue functions. [46]

In recent years, the field of molecular glues has witnessed an explosion of discoveries targeting native proteins. [47] Examples include synthetic FKBP12-binding glues like FKBP12-rapadocin, which targets the adenosine transporter SLC29A1. [47] Thalidomide and lenalidomide, classified as immunomodulatory drugs (IMiDs), were identified as small-molecule glues inducing ubiquitination of transcription factors via E3 ligase complexes. [47] Computational searches for molecular-glue degraders since 2020 have added novel probes to the ever-expanding landscape of molecular glues. [47] [52] Furthermore, computational methods are starting to shed light onto molecular glues mechanisms of action. [52]

The transformative power of molecular glues in medicine became evident as drugs like sandimmune, tacrolimus, sirolimus, thalidomide, lenalidomide, and taxotere proved effective. [47] The concept of inducing protein associations has shown promise in gene therapy and has become a potent tool in understanding cell circuitry. [47] As the field continues to advance, the discovery of new molecular glues offers the potential to reshape drug discovery and overcome previously labeled "undruggable" targets. [47] The future of molecular glues holds promise for rewiring cellular circuitry and providing innovative solutions in precision medicine. [47]

Challenges and future prospects

While molecular glue compounds hold great potential in various fields, there are challenges to overcome. Ensuring the specificity of these compounds and minimizing off-target effects is essential. Additionally, understanding the long-term consequences of manipulating protein interactions is crucial for their safe and effective application in medicine.

Ongoing research in molecular glue is unlocking new compounds and insights into their mechanisms. With an expanding understanding of protein-protein interactions, molecular glue holds significant promise across biology, medicine, and chemistry, potentially revolutionizing cellular processes and advancing innovative disease treatments. As this field progresses, it may open new therapeutic avenues and deepen our understanding of life's molecular intricacies.


References

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