Molecular glue mechanism. Overall, we hope to explain the general law .

Molecular glue mechanism Sep 13, 2025 · The use of molecular glues to modulate protein–protein interactions has emerged as a promising approach to drug previously intractable targets. Sep 20, 2024 · Unlike conventional small-molecule drugs that target a single protein, molecular glues are a type of small molecules that function by enhancing the affinity between two proteins, thus inducing protein-protein interaction (PPI) between them. These small-molecule MGs are gradually being recognized for their potential application in treating human diseases, including cancer. Explore challenges & opportunities in molecular glues discovery with our specialized platform. This study provides a framework to investigate the mechanisms of covalent small molecule ligation and informs (covalent) molecular glue development. A major focus of the Sperling lab is studying the mechanism of action of protein degraders. 1. The concept of molecular glue is not novel; the term was used in the late 1980s to refer to small molecules or proteins that induce fusion of protoplasts or allow platelet aggregation. 1C). ' [1] Ub = ubiquitin; R = Rbx1; E2 = E2 ubiquitin-conjugating enzyme. (A) Difference of orthosteric regulator, allosteric regulator and molecular glue. ABA is a sesquiterpene phytohormone Thus, the versatility of molecular glues gives them longevity in drug discovery. Despite advantages such as cell permeability and the potential for low off-target activity Jul 12, 2023 · The intracellular interactions of biomolecules can be maneuvered to redirect signaling, reprogram the cell cycle, or decrease infectivity using only a few dozen atoms. As alluded to above, the term molecular glue encompasses molecules that manipulate PPIs with divergent mechanisms of action and with contrasting functional consequences. However, we currently lack rational chemical design principles for converting protein-targeting ligands into molecular glue degraders. This review aims to offer valuable insights for future studies in this field. May 12, 2022 · Molecular glues and molecular glue degraders and their mechanism of action. Jun 1, 2022 · Molecular glue (MG) compounds are a type of unique small molecule that can change the protein–protein interactions (PPIs) and interactomes by degrading, stabilizing, or activating the target protein after their binging. May 2, 2024 · Konstantinidou and Arkin review a decade of the evolution of molecular glues—molecules that modulate protein-protein interactions by inducing proximity. Given that molecular glue research is still in its early stage, we summarized the mechanisms of molecular glue, the promising drugs in clinical trials and diverse feasible design strategies for molecular glue therapeutics. Feb 18, 2025 · The asymmetric KBTBD4 dimer assembly and unexpected dual-glue mechanism are reminders that emerging molecular-glue mechanisms are almost certain to include departures from the current model. ABA is a sesquiterpene phytohormone A category for drugs with molecular glue or glue-like mechanisms of action. Aldehyde-based molecular glue activity is initially regulated by cooperative non-covalent binding, followed by slow covalent ligation, further enhancing stabilization. May 1, 2025 · Here, the authors described the discovery of PVTX-405 as a potent, highly selective, and orally efficacious IKZF2 molecular glue degrader and their preclinical data support the clinical Dec 9, 2019 · Thus, the new structures demonstrate that molecular-glue targeting of regular secondary structures is possible. 29 The molecular glue degraders such as thalidomide were discovered retrospectively, after their FDA approval and later detection of their immunomodulatory and Feb 21, 2024 · Thus, despite being structurally differentiated, IBG4 phenotypically mimics the cellular mechanism of action of IBG1, suggesting that both compounds share an intramolecular glue-like mechanism. Apr 4, 2022 · Examples of molecular glue degraders include thalidomide, lenalidomide, and pomalidomide. Jul 19, 2021 · Mechanisms of molecular glue induced degradation that bypass recruitment of an E3 ligase receptor. As a torrent of new molecular-glue probes and medicines are fueling interest in this field, I explore the arc of this story. Jun 19, 2025 · This effect is akin to that of other molecular glue-like compounds that promote the dimerization or oligomerization of target proteins, positioning verteporfin as a molecular glue activator of IRE1α. We provide a comprehensive overview of both, comparing their mechanisms of action, advantages, disadvantages, and broader implications in drug development. They thus enable selective degradation of undruggable targets in cancer and beyond. Whilst some monovalent glue degraders have been found through serendipity, the rules for small molecule attributes and the pairs or complexes of proteins that are Apr 15, 2024 · CRBN is a substrate receptor for the Cullin Ring E3 ubiquitin ligase 4 (CRL4) complex. ② Mechanism Differences: The main difference between PROTACs and molecular glue lies in their mechanisms of action. Hand-in-hand, synthetic chemistry and biology are rapidly diversifying the biochemical space of induced protein interactions. Apr 24, 2024 · Therefore, molecular glue has the potential to alter a range of biological processes, including transcription, translation, protein folding, and degradation. Apr 16, 2024 · Molecular glues are small molecules that help target unwanted proteins for destruction in the cell’s ubiquitin-proteasome system. 1 day ago · A molecular glue induces CRBN homodimerization and degradation through degron mimicry, revealing a distinct glue mechanism and offering a tool to study CRBN biology. By facilitating protein–protein interactions between E3 ubiquitin ligases and neo-substrates, MGDs offer a novel approach to target previously undruggable or insufficiently drugged disease-causing proteins. In contrast, molecular glues refer to monovalent small molecules that rely on the secondary structural characteristics Jan 7, 2021 · 2021 marks the 30th anniversary of the revelation that cyclosporin A and FK506 act in a way previously not seen—as “molecular glues” that induce neo-protein–protein associations. The CRL4CRBN E3 ubiquitin ligase is the target of molecular glue degrader compounds that reprogram ligase specificity to induce the degradation of clinically relevant neosubstrate proteins. It has been observed that CRBN can be exploited by small molecules to facilitate the recruitment and ubiquitination of non-natural CRL4 substrates, resulting in the degradation of neosubstrate through the ubiquitin–proteasome system. Jul 29, 2024 · Our studies reveal a class of molecular glue degraders that act through template-assisted covalent modification and establish a mechanism for how trans -labeling can stabilize a molecular glue Apr 10, 2024 · Molecular Glue Mechanism of Action Molecular glues are a class of small-molecule compounds that influence the interactions between proteins through a unique mechanism. Molecular glue degraders are a class of protein degraders that operate by recruiting target proteins to cellular degradation machinery via noncanonical protein-protein interactions, inducing the destruction of the target protein. Mar 25, 2025 · Molecular glue (MG) degraders, small molecules with significant therapeutic potential for targeting undruggable proteins, are emerging as new modality in drug discovery. Classifying Molecular Glues Based on Approved Drugs. Recently, the emergence of low-molecular-weight molecular glue degraders (MGDs) has expanded the TPD landscape, because MGDs operate via the same mechanism while offering attractive physicochemical properties that are consistent with small-molecule therapeutics. Jul 20, 2022 · Mechanism of action, structure–activity relationship, and protein–molecular glue interaction studies of initially discovered molecular glues have laid the foundation for their optimization using structure-based drug design (SBDD). The molecular glue of BMS has reached an annual sales volume of 12. Mechanisms of Action: How Molecular Glue Degraders Work Molecular glue degraders can mediate PPIs through a variety of mechanisms, each with unique implications for protein function and therapeutic intervention. 3. Figure 1. While PROTACs rely on heterobifunctional motifs, MGDs possess more compact, mono-affinitive molecular structures, offering distinct advantages in drug-like The concept of molecular glues Molecular glues induce a novel interaction between two proteins and form a ternary complex, leading to diverse biological and pharmacological functions. Aug 21, 2022 · The ultimate goal—being able to find a molecular glue for any protein target—may still be far off, but systematic approaches for finding glues are yielding new clinical candidates. 8 Nov 1, 2024 · This ubiquitin-mediated degradation pathway was first harnessed by bivalent degraders. Apr 14, 2025 · Strategy of TRIM21-based molecular glue and PROTAC degraders. 6 Molecular glue degraders have been serendipitously discovered and interact with a variety of target proteins "molecular glue" was initially coined to describe the mechanism of action of cyclosporin A and FK506 inducing novel protein–protein associations. This phenomenon, known as molecular glue-induced protein degradation, has May 31, 2023 · Aldehyde-based molecular glue activity is initially regulated by cooperative non-covalent binding, followed by slow covalent ligation, further enhancing stabilization. (B) Schematic diagram of divalent molecular interaction mode. Find out how microplate readers can advance research into molecular glue degraders. Jun 4, 2025 · This effect is akin to that of other molecular glue-like compounds that promote the dimerization or oligomerization of target proteins, positioning verteporfin as a molecular glue activator of IRE1α. Jul 14, 2025 · The systematic identification of new chemical matter with a molecular glue mechanism of action remains a significant challenge in drug discovery. Dec 27, 2022 · Figure 2. Here, we review the methods and approaches that have led to the identification Jan 10, 2025 · The versatile nature of molecular glue–protein interactions provides significant potential for the advancement of small-molecule molecular glues, which can serve as valuable tools for understanding disease mechanisms and enhancing drug development, particularly for treating cancer. Sep 1, 2022 · This review discusses representative cases of molecular glues and analyzes the binding mode of the molecular glue–protein complex. Based on the aggregation mode of molecular glues mediating protein–protein interactions, three mediating modes including homo-dimerization, homo-polymerization and hetero-dimerization are reviewed in detail (Fig. Overall, we hope to explain the general law Jul 24, 2025 · Induced proximity by molecular glues is a strategy that leverages the recruitment of proteins to facilitate their modification or degradation. Detailed examples highlight the diverse opportunities for molecular glues in drug discovery. png). Profiling the E3 ligase interactome induced by MG degraders provides insights into their mechanism of action and identifies clinically relevant neosubstrates for degradation, thereby offering new therapeutic opportunities Jul 28, 2021 · Targeted protein degradation is a promising area in the discovery and development of innovative therapeutics. This novel approach opens up new avenues for Dec 15, 2023 · In contrast, molecular glue discovery and design requires new screening strategies that induce proximity. The mechanism of molecular glues is prevalent in nature, with abscisic acid (ABA) being one of the best-known examples. The authors emphasize key features of molecular recognition and cooperative binding, providing insights toward systematic discovery and optimization. Here, we present an overview of recently reported MGDs, highlighting their Jul 18, 2025 · Realising the promise of new medicines that operate through a targeted molecular glue-induced degradation mechanism requires systematic tools that can uncover the relevant principles of neomorphic protein-protein interactions. Jul 3, 2025 · Molecular glue degraders (MGDs) are an emerging modality for targeting proteins intractable by classical small-molecule drugs, such as transcription factors relevant in cancer. To achieve this, we leverage known molecular glue-mediated ternary complexes and derive a rationale for the in-silico design of molecular glues. Explore the principles, mechanisms, and advantages of molecular glues in our blog, delving into their impact on drug design and cancer therapy Apr 29, 2024 · Molecular glues are an underrepresented mode of drugging protein interaction, function, and stability. Historically, research on TCM has mainly focused on exploring the mechanisms of active components acting on single targets. SUMMARY Small molecule molecular glues can nucleate protein complexes and rewire interactomes. Such “molecular glues,” which can drive both novel and known interactions between protein partners, represent an enticing therapeutic strategy. explore the concepts and advances of molecular glue design, discovery, and screening platform technologies. Mode of action and structural features of molecular glue and PROTAC. In recent years, the emergence of molecular glues (MGs) theory has provided Molecular Glue Mechanism of Action- The schematic describes the action of a Molecular Glue molecule (MG) that binds to an E3 ligase and induces E3 interaction with a specific target protein (T). Jan 1, 2022 · We refer to these compounds as ‘orphan’ molecular glues since their presenter protein is clear (here an FKBP, strongly suggesting a molecular glue mechanism), but the ternary target partner is unknown. The mechanism of molecular glues hinges on their ability to exploit existing protein surfaces or interfaces. Molecular glues mediate proximity-induced protein degradation and have intrinsic advantages over heterobifunctional proteolysis-targeting chimeras, including unprecedented mechanisms, distinct biological activities, and favorable physicochemical properties. In the widely accepted mechanism, a molecular glue stabilizes two proteins within a ternary complex – here we show how differences in Mar 31, 2025 · Molecular glue degraders offer a smaller, more drug-like alternative to PROTACs. D Molecular glue degraders induce the interaction of an E3 ubiquitin ligase with a protein target. The principle underlying the action of molecular glues lies in their capacity to 'glue' together proteins, thereby influencing cell signaling pathways and physiological processes. Aug 3, 2020 · Classified by their mechanism of action, there are three types of degrader molecules: bivalent degraders commonly known as PROTACs, monovalent degraders, and molecular-glue degraders (Fig. 1: Mechanism of molecular glue induced substrate recruitment to CRL4. Proximity-induced targeted protein degradation and molecular glues Molecular glues are monovalent small molecules (<500 Da) that chemically induce the proximity of target proteins with E3 ubiquitin ligases to ubiquitinate and degrade specific proteins via the proteasome (Figure 1A). Novel approaches to degrad-ing therapeutic targets using molecular-glue degraders and PROTACs are emerging in pharmaceutical and biotech-nology companies, and the drug-discov-ery process is being reshaped to overcome what was previously labeled as undruggable through the actions of molecular glues. Dec 10, 2024 · The cancer mutations resemble chemical glue UM171 functionally, structurally, and mechanistically, elucidating the converging mechanisms between molecular glue degraders and cancer gain-of-function mutations, portraying cancer mutations as "genetic glues. The discovery of drugs that work as molecular glues has enabled therapeutic targeting of non-enzyme Aug 9, 2024 · Molecular glue degraders (MGDs) are a class of molecular glues that stick a target protein to an E3 ligase complex, leading to the protein’s ubiquitination and subsequent degradation by the proteasome. Apr 1, 2025 · The mechanism of action of traditional Chinese medicine (TCM) remains unclear. Molecular glues have been identified with various other mechanisms of action, including autophagy-mediated protein degradation, MEK sub-complexes stabilization, KRAS mutant inhibition, α-tubulin polymerization Jul 7, 2025 · Molecular glues powerfully control protein proximity but have largely eluded direct screening. Feb 1, 2024 · The purpose of this review is to introduce current understanding of antitumor mechanism of molecular glues targeting GSPT1, provide a summary of the pharmacology profiles of existing molecular glues, and outline development strategies of novel molecular glues. A promising avenue for addressing this challenge lies within pinpointing the fundamental features for function-first identification of molecular gluing events. To overcome this challenge, we sought to identify Oct 27, 2023 · RMC-6236 has a novel mechanism of action, as it is a molecular glue that binds together 2 proteins, cyclophilin A and KRAS, which do not typically interact with one another, Garrido-Laguna says. Molecular glue Auxin's mechanism of action, which led to the popularization of the term 'molecular glue. A molecular glue is a type of small molecule that modulates protein–protein interactions in cells by enhancing the affinity between proteins. Dec 12, 2024 · This marks a revolutionary advancement in the landscape of small molecule drugs. Dec 19, 2024 · Of the various TPD technologies, molecular glue degraders and proteolysis-targeting chimeras (PROTACs) stand out for their unique mechanisms and potential therapeutic applications. Most molecular glues are expected to form interactions between protein molecules (intermolecular), but interactions within a single protein (intramolecular) have also been described, which show glue-like behaviour. Unlike traditional small-molecule inhibitors, which block a protein's active site, molecular glues work by bringing two proteins together, thereby altering their function. Aug 21, 2025 · Abstract Molecular glue degraders (MGDs) and proteolysis-targeting chimeras (PROTACs) are two prominent approaches in targeted protein degradation, both leveraging the ubiquitin-proteasome system to induce selective protein degradation. Molecular glues can A enhance and stabilize protein interactions, B repair protein interactions weakened by mutations or C induce de novo protein interactions. Mar 8, 2023 · The molecular glue mechanism of action is quite alluring, as it enables the targeting of proteins otherwise considered “undruggable. Molecular glues are widely used as probes for understanding functional proximity at a systems level, and the potential to instigate event-driven pharmacology has motivated their application as therapeutics. Jun 20, 2024 · As shown here with multiple examples, the solvent-exposed parts of the molecules, although typically considered of minor importance, were actually fundamental for molecular recognition and the glue-like mechanism of action. (S)-ACE-OH, a metabolite derived from the antipsychotic drug acetophenazine, functions as a molecular glue degrader of the nuclear pore complex. ” This type of research is now surging through the biotech community, as scientists are attempting to discover and develop molecular glues to target and degrade a myriad of disease-causing proteins that until May 31, 2023 · Aldehyde-based molecular glue activity is initially regulated by cooperative non-covalent binding, followed by slow covalent ligation, further enhancing stabilization. The molecular glue first binds a presenter protein, creating a neo-protein with enhanced affinity for a target protein (Figure 1 A, top Jan 2, 2025 · Molecular glue degraders (MGDs) represent a unique class of targeted protein degradation (TPD) modalities. Nov 11, 2024 · This groundbreaking finding demonstrated that molecular glues could be harnessed to control intracellular signaling pathways. " Aug 3, 2020 · In summary, the presented data provides a rational and scalable framework for the discovery of cellularly active molecular glue degraders with established and nonobvious mechanisms of action. Despite strong interest in this modality, a comprehensive theoretical framework is lacking. 1a) 1, 2. Selected examples of disclosed CRBN-based molecular glue degrader drugs, clinical candidates, and preclinical candidates from the 2022 CAS Insights article and the 2022 Biochemistry article. Innovative approaches for protein degradation & novel therapeutic mechanisms. These drugs work by a unique mechanism in that they act as a molecular bridge or glue to bring together proteins or macromolecular complexes that would not otherwise interact (Image: Molecular glue. Mechanism of action, structure–activity relationship, and protein–molecular glue interaction studies of initially discovered molecular glues have laid the foundation for their optimization using structure-based drug design (SBDD). The E3 ligase modulator (CRBN) is highlighted in purple and the protein targeting moiety is highlighted in green. We have established a complete mechanistic analysis which enables the determination of molecular glues’ binding and cooperativity values from a simple Jun 20, 2024 · Molecular glues such as rapamycin and FK506 exemplify the latter two examples; through a glue mechanism, rapamycin induces a single serine dephosphorylation of its target mTOR 6 and both rapamycin and FK506 are concentrated in enucleated red blood cells, 7 which have high concentration of their presenter protein FKBP12. . Molecular glue degrader (MGD): a small molecule that facilitates the targeted degradation of speci ficproteins by promoting from the interaction between protein of interest and an E3 its anti-ligase. Apr 29, 2024 · Two distinct classes of protein degradation therapeutics are being widely explored: bifunctional PROTACs and molecular glue degraders, both of which have their unique advantages and challenges. (C) Schematic diagram of molecular interaction mode and classification of protein polymerization patterns induced by molecular glues. In this review, Robinson et al. May 8, 2025 · Molecular glue–antibody conjugates (MACs) are a novel class of antibody–drug conjugates (ADCs) that utilize molecular glues as payloads and exhibit distinct cell-killing mechanisms compared with cytotoxic agents. Evidence suggests that small-molecule MG Apr 11, 2023 · Targeted protein degradation with molecular glue degraders has arisen as a powerful therapeutic modality for eliminating classically undruggable disease-causing proteins through proteasome-mediated degradation. Jun 23, 2024 · A molecular glue is a type of small molecule that facilitates the interaction between two distinct proteins, often creating a new connection or stabilizing an existing one. Jan 24, 2025 · Structural elucidation of E3 ligase in complex with molecular glue and the target of interest, combined with computational modeling, facilitates the understanding of the underlying mechanisms of how molecular glues induce targeted degradation. 69 Interestingly, they have been approved by the FDA for the treatment of various types of tumors long Unlike conventional small-molecule drugs that target a single protein, molecular glues are a type of small molecules that function by enhancing the affinity between two proteins, thus inducing protein-protein interaction (PPI) between them. Profiling the E3 ligase interactome induced by MG degraders provides insights into their mechanism of action and identifies clinically relevant neosubstrates for degradation, thereby offering new therapeutic opportunities Jun 20, 2024 · Small molecule molecular glues can nucleate protein complexes and rewire interactomes. Known cereblon (CRBN) neosubstrates share a generalizable β- Mechanism of action, structure−activity relationship, and protein−molecular glue interaction studies of initially discovered molecular glues have laid the foundation for their optimization using structure-based drug design (SBDD). Keywords: molecular glue degrader, tumor, design strategies, mechanism, clinical trials Jun 21, 2022 · Molecular glues of varying types have been discovered; the best known is probably thalidomide and its analogs, and lenalidomide and pomalidomide, which target the E3 ligase cereblon. Despite advantages such as cell permeability and the potential for low off-target activity, glues are Jul 30, 2025 · Inspired by natural molecular glues, drug hunters are chasing protein–protein interactions with next-gen small molecules tuned for enhanced tissue specificity and reduced toxicity. Here the authors present unbiased quantitative Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. Nov 11, 2024 · This Scientific Reports Collection welcomes original research on molecular glues, from biochemical to clinical studies, aiming to highlight their potential in medical and pharmaceutical research. Sep 11, 2023 · By investigating the structure–activity relationship of molecular glue degraders that target cyclin K, we discovered that a wide range of compounds, including known kinase inhibitors, possess Aug 16, 2023 · Molecular glue degraders offer new opportunities for therapeutic development beyond current applications of immunomodulatory drugs, which can expand to nonhematological solid tumors, inflammation, autoimmunity, neurologic disorders, and genetic and metabolic diseases. (A) CR8 hijacks the E3 ligase adaptor, DDB1, as opposed to the E3 receptor, to position cyclin K in the ubiquitination zone, promoting its proteasomal degradation. Mar 6, 2024 · Molecular glue degraders recruit target proteins to ubiquitin ligase enzymes, which attach ubiquitins that deliver the target for disposal. Compared to PROTACs, molecular glue degraders tend to have chemical properties Feb 24, 2024 · Targeted protein degradation (TPD) primarily degrades target proteins through the ubiquitin-proteasome and lysosome, and according to the specific mechanism of action, it can be further subdivided into nearly 10 different technical routes, among which the fastest developing are molecular glue and Protein Degrader technology. However, it is insufficient to explain the complex mechanisms by which these active components in TCM treat diseases. Feb 10, 2022 · “Molecular glue” (MG) is a term coined to describe the mechanism of action of the plant hormone auxin and subsequently used to characterize synthetic small molecule protein degraders Feb 5, 2025 · In this work, we aim to establish an in-silico method for designing molecular glues. Mar 17, 2025 · For instance, the molecular glue MRT-6160 is currently being evaluated for its ability to degrade VAV1 in immune-mediated conditions; its mechanism involves the targeted degradation of key signaling proteins that contribute to cytokine-mediated inflammation. Mar 1, 2024 · In contrast, molecular glue discovery and design requires new screening strategies that induce proximity. Classical molecular glue Jun 20, 2024 · A defining feature of molecular glues, first identified in efforts to understand the mechanism of action of natural products FK506, cyclosporin, and rapamycin, 1,2,3 is their ability to induce ternary and higher-order complex formation cooperatively. 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