Stuck Like Glue: Molecular Glue Discovery & Development

Molecular glue discovery and development represents an exciting area of therapeutic innovation with the potential to revolutionize treatment options for a range of human diseases. But what exactly are molecular glues, and what do they add to the clinical arsenal? Check out this blog post to learn more about molecular glues, including what they do, why they are important, and how they can be effectively discovered and developed into potent, selective therapeutics.

What is a molecular glue?

Molecular glues are small-molecule compounds that induce the degradation of a target protein or otherwise modify its activity by creating or enhancing protein-protein interactions (PPIs). This general mechanism is referred to as induced proximity. Molecular glue degraders can function in a similar manner to other targeted protein degrader modalities: by promoting proximity between the target protein and an E3 ligase, which ubiquitinates the target and triggers its degradation. However, targeted protein degraders are typically heterobifunctional molecules, in which one domain engages with the target and a second, linked domain recruits the E3 ligase. In contrast, molecular glue degraders modify binding interfaces to induce ‘neo-associations’ between E3 ligases and their ‘neo-substrates’.

Not all molecular glues act via this degradation-based mechanism. For example, the molecular glue rapamycin acts by inducing binding between FKBP1A and the kinase mTOR. This novel interaction inhibits the activity of mTOR and modulates downstream signaling pathways, ultimately leading to immunosuppressant effects. Other molecular glues act within a single protein or protein complex, stabilizing an inactive conformation to ablate or reduce target activity.

What value do molecular glues offer as therapeutics?

In a therapeutic context, molecular glues act to induce the degradation of a target protein or to modulate its activity in some way. These basic capabilities can be applied to a diverse range of cellular targets to intervene in various disease processes. Molecular glue degraders share many properties with other types of targeted degraders; they can be effectively applied to traditionally ‘undruggable’ targets and act in a substoichiometric fashion, meaning that relatively low treatment doses can induce sustained therapeutic effects. However, molecular glue degraders also offer unique advantages over traditional targeted protein degraders, including their small size, permeability, and overall compliance with Lipinski’s rule of five. Non-degrading glues share these pharmacological benefits, while also avoiding the need to rely on endogenous degradation pathways. Furthermore, non-degrading glues enable the ‘fine-tuning’ of target activity and offer the potential for reversible pharmacology.

How have molecular glues historically been discovered?

Early molecular glues were discovered serendipitously and largely without an understanding of their mechanism of action. Such compounds were only later, after in-depth characterization efforts, determined to exert their therapeutic effects by functioning as molecular glues. Examples of early molecular glues include cyclosporin A, rapamycin, thalidomide, and lenalidomide. Cyclosporin A treatment leads to the formation of a cyclophilin-calcineurin complex, blocking calcineurin’s phosphatase activity to disrupt downstream signaling pathways. Rapamycin exerts an analogous effect by inducing complex formation between FKBP1A and mTOR, inhibiting the latter’s kinase activity. These compounds are, therefore, examples of non-degrader molecular glues. Thalidomide and lenalidomide, in contrast, bind to the E3 ligase cereblon (CRBN), modifying its binding surface to enable interactions between CRBN and neo-substrates. These neo-substrates, including the zinc-finger transcription factors IKZF1 and IKZF3, are ubiquitinated by CRBN and subjected to proteasomal degradation.

What modern approaches can advance molecular glue discovery and development?

A key challenge in molecular glue development is the efficient discovery of lead compounds. An effective molecular glue must not only bind two relevant protein targets but do so in a way that either triggers proteasomal degradation (as when one of the targets is an E3 ligase) or modulates the stability or functional activity of at least one target. These effects must also be selective, with the induced degradation or inhibition limited to the desired target protein.

Affinity selection mass spectrometry (ASMS) is one powerful approach for the discovery of both degrading and non-degrading molecular glues. This high-throughput, label-free screening approach can be used to identify direct binders of a selected E3 ligase, such as VHL or cereblon (CRBN). Using a combined screen/counterscreen approach, ASMS can also be used to identify candidate ligands binding any two protein partners. In this workflow, target proteins are screened in tandem to identify all complex binders, then screened individually; individual hits are excluded, and only compounds that uniquely bind the complex are progressed for validation and optimization.

Following hit discovery, a variety of techniques can be leveraged to support the prioritization and development of promising molecular glues. For degrader glues, proteomic profiling technologies – such as ProteomeScout™HT – can be used to confirm target protein degradation and assess treatment specificity on a global level. Degrader development can also be supported by assays like UbiScout™ and TurnoverScout™, which enable ubiquitination and subsequent degradation to be assessed across the proteome. For both degrader and non-degrader glues, SPICE and similar target engagement assays can provide valuable biophysical evidence of complex formation and stabilization.

Click here to learn more about Momentum’s services to support molecular glue discovery and development. When you’re ready to connect with our scientific team and explore how we can help advance your molecular glue research program, send us a message.

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