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Molecular glue

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Auxin's mechanism of action, which led to the popularization of the term 'molecular glue.'[1] Ub = ubiquitin; R = Rbx1; E2 = E2 ubiquitin-conjugating enzyme.

Molecular glue refers to a class of chemical compounds or molecules that play a crucial role in binding and stabilizing protein-protein interactions in biological systems. These molecules act as "glue" by enhancing the affinity between proteins, ultimately influencing various cellular processes. Molecular glue compounds have gained significant attention in the fields of drug discovery, chemical biology, and fundamental research due to their potential to modulate protein interactions, and thus, impact various cellular pathways. They have unlocked avenues in medicine previously thought to be "undruggable".

History

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The concept of "molecular glue" originated in the late 20th century, with immunosuppressants like cyclosporine A (CsA) and FK506 identified as pioneering examples.[2] 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.[3] By 1979, CsA was used clinically, and FK506 (tacrolimus), discovered in 1987 by Fujisawa, emerged as a more potent immunosuppressant.[3] 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.[3] 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.[3] 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.[3] The creation of synthetic "chemical inducers of proximity" (CIPs), such as FK1012, opened the door to more complex molecular glues.[3] Rimiducid, a purposefully synthesized molecular glue, demonstrated its effectiveness in eliminating graft-versus-host disease by inducing dimerization of death-receptor fusion targets.[3]

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.[3] 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.[3]

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.[4] 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.[5] 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.[6] 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.[2] 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.[2][3] Subsequently, indisulam was identified as a molecular glue capable of degrading RBM39 by targeting DCAF15 in 2017.[2] 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.[7] 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.[2] Additionally, chemogenomic screening revealed structurally diverse molecular glue degraders targeting cyclin K.[2] The discovery that manumycin polyketides acted as molecular glues, fostering interactions between UBR7 and P53, further expanded the understanding of molecular glue functions.[2]

In recent years, the field of molecular glues has witnessed an explosion of discoveries targeting native proteins.[3] Examples include synthetic FKBP12-binding glues like FKBP12-rapadocin, which targets the adenosine transporter SLC29A1.[3] Thalidomide and lenalidomide, classified as immunomodulatory drugs (IMiDs), were identified as small-molecule glues inducing ubiquitination of transcription factors via E3 ligase complexes.[3] Computational searches for molecular-glue degraders since 2020 have added novel probes to the ever-expanding landscape of molecular glues.[3][8] Furthermore, computational methods are starting to shed light onto molecular glues mechanisms of action.[8]

The transformative power of molecular glues in medicine became evident as drugs like sandimmune, tacrolimus, sirolimus, thalidomide, lenalidomide, and taxotere proved effective.[3] The concept of inducing protein associations has shown promise in gene therapy and has become a potent tool in understanding cell circuitry.[3] 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.[3] The future of molecular glues holds promise for rewiring cellular circuitry and providing innovative solutions in precision medicine.[3]

Properties and mechanisms

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Molecular glue compounds are typically small molecules that can bridge interactions between proteins. They often have specific binding sites on their target proteins and can enhance the association between these proteins. They do so by changing the surfaces of the proteins, encouraging binding between them when they would not usually interact. Molecular glue can enhance the stability of protein complexes, making them more resistant to dissociation. This can have a profound impact on cellular processes, as many biological functions are carried out by protein complexes. By influencing protein-protein interactions, molecular glue can modify the functions, localization or stability of the target proteins. This can lead to both therapeutic and research applications.[9]

In the current era, molecular glues have become a more commonly utilized approach for targeted protein degradation, offering advantages over traditional small molecule drugs and PROTACs. The recognition of substrates by E3 ubiquitin ligases, governed by protein-protein interactions (PPIs), plays a critical role in cellular function.[10] There is significant therapeutic potential in developing small molecules that modulate these interactions, especially in the context of hard-to-drug proteins. A recent study reported the identification and rational design of potent small molecules acting as molecular glues to enhance the interaction between an oncogenic transcription factor, β-Catenin, and its cognate E3 ligase, SCFβ-TrCP.[10] These enhancers demonstrated the ability to potentiate ubiquitylation and induce the degradation of mutant β-Catenin both in vitro and in cellular systems. Unlike PROTACs, these drug-like small molecules insert into a naturally occurring PPI interface, optimizing contacts for both the substrate and ligase within a single molecular entity.[10]

Molecular glues offer a unique advantage in degrading non-ligand-bound proteins by promoting the PPI between ubiquitin ligase and the target protein.[10] Notably, molecular glues exhibit superior therapeutic effects compared to small molecule drugs. This is attributed to their lower molecular weight, higher cell permeability, and better oral absorption, aligning with the "Five Rules for Drugs".[10] In contrast, PROTACs face challenges such as high molecular weight, poor cell permeability, and unfavorable pharmacokinetic characteristics, hindering their clinical development.[10]

Recent advances in the field have led to the development of BCL6 and Cyclin K Degraders, which leverage both protein-ligand and protein-protein interfaces for tight complex formation.[11] These molecular glue degrader drugs are characterized by their small size (<500 Da) and exhibit high affinity between the ligase and neosubstrate in the presence of the small molecule.[11] The complementary nature of protein-protein interfaces suggests the potential for natural interactions between the two proteins even in the absence of the compound.[11]

The identification of molecular-glue-type degraders has typically occurred retrospectively and serendipitously, but recent chemical-profiling approaches aim to prospectively identify small molecules acting as molecular glues.[12] Researchers are exploring alternative small molecules, like CR8, to induce ubiquitination of targets in a top-down approach for induced protein degradation.[13] CR8, identified through correlation analysis, operates via protein degradation by inducing ubiquitination through a molecular glue-like mechanism. The study emphasizes the potential of small molecules beyond PROTACs for targeted protein degradation.[13]

There have also been reports of molecular glues that stabilize protein-RNA interactions[14] and protein-lipid interactions.[15]

Applications

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Cancer therapy

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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

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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

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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

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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]

Challenges and future prospects

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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.

Examples

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Cyclophilin

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FKBP12

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Other

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Degraders

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CRBN

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=

Other

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References

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