Targeted protein degradation (TPD) exploits induced proximity to recruit cellular degradation machinery and eliminate disease-relevant proteins, while non-degrading molecular glues induce or stabilize protein interactions to modulate activity without protein loss. Together, these approaches expand the druggable proteome and enable precise, catalytic, and context-dependent control of cellular pathways.
Among the most prominent TPD modalities are proteolysis-targeting chimeras (PROTACs) and molecular glue degraders, both of which induce proximity between a target protein and an E3 ubiquitin ligase to trigger ubiquitination and subsequent proteasomal degradation.
Continued innovation in these modalities is expected to significantly impact drug discovery by enabling selective and durable modulation of proteins previously considered undruggable.
PROTACs
PROTACs are heterobifunctional small molecules composed of three distinct elements: a ligand that binds the protein of interest, a ligand that recruits an E3 ubiquitin ligase, and a chemical linker connecting the two.
By simultaneously engaging both proteins, PROTACs promote the formation of a ternary complex that enables catalytic, event-driven degradation of the target protein. This mechanism allows PROTACs to achieve sustained biological effects at sub-stoichiometric concentrations and to overcome resistance mechanisms associated with target overexpression or mutation.
Since their initial conceptualization, PROTACs have been rapidly optimized for potency, selectivity, and pharmacokinetic properties, with several candidates advancing into clinical development.
Molecular glue degraders
Molecular glue degraders are typically monovalent, low-molecular-weight compounds that stabilize or induce novel protein–protein interactions between an E3 ligase and a target protein.
Rather than physically linking two binding moieties, molecular glues reshape the surface of one protein—often the E3 ligase—to create a complementary interface for the target, thereby facilitating ubiquitination.
Classic examples include the immunomodulatory drugs (IMiDs), which redirect the CRBN E3 ligase to degrade neosubstrates such as IKZF1 and IKZF3. Although their discovery has often been serendipitous, advances in structural biology and chemoproteomics are increasingly enabling the rational identification and design of molecular glue degraders.
Non-degrading molecular glues
Non-degrading molecular glues are small molecules that function by stabilizing or inducing protein–protein interactions without engaging the ubiquitin–proteasome system.
They reprogram a protein behavior by bringing it into proximity with a binding partner, leading to changes in activity, localization, complex formation, or downstream signaling. This proximity-driven mechanism enables modulation of protein function that is difficult or impossible to achieve through traditional inhibition.
Because their effects depend on the continued presence of the molecule, non-degrading molecular glues offer reversible and tunable control over biological processes. They are particularly valuable for regulating transcription factors, scaffolding proteins, and signaling adaptors where partial or context-specific modulation is preferred over complete protein loss.
Edelris Library production platform to generate E3-ligase biased collections
Since 2017, beginning with a first collaboration with Craig Crews at Yale, Edelris has been a pioneer in the development of E3-ligase-biased libraries. This initial partnership was followed by exclusive collaborations with leading biotech and pharmaceutical organizations. Our platform relies on proprietary technologies and expertise in high-throughput synthesis and purification, supported by standardized processes that ensure high productivity and reliable, regular delivery to our customers.
Exploration of Novel CelMods derived from Edelris Keymical Space allowed identification of new CRBN small-molecule binders (tSNE plot of Virtual Keymical space of 30,000 compounds shows several novel clusters, synthesized representative compounds showed micromolar binding by HTRF assay against CRBBN-DDB1 complex)
In addition to supporting client-driven designs, Edelris has explored its proprietary Keymical Space to create novel, patentable degraders. As a representative example, we identified new CRBN small-molecule binders from a virtual, CELMoD-library of 30,000 compounds, derived from our unique know-how. These newly discovered series provide a strong starting point for the generation of expanded libraries for evaluation in protein degradation assays.
ASMS Screening Strategies to discover new E3-ligase warheads
The discovery and development of new E3-ligase ligands is a critical driver of next-generation proximity-induced therapeutics. While early targeted protein degradation strategies have relied heavily on a small number of well-characterized E3 ligases, such as CRBN and VHL, the human genome encodes more than 600 E3 ligases, most of which remain untapped for drug discovery. Expanding the repertoire of E3-ligase ligands enables greater control over tissue selectivity, degradation kinetics, and target scope.
New E3-ligase ligands provide opportunities to tailor proximity-based mechanisms by engaging ligases with distinct expression patterns, subcellular localizations, and regulatory properties. The systematic exploration of novel E3-ligase binders is emerging as a foundational strategy to unlock the full potential of targeted protein degradation and broader proximity-induced drug discovery.
ASMS is a powerful, privileged technology for exploring novel E3 ligases and identifying ligands that can serve as new warheads for PROTAC or molecular glue drug discovery. Edelris has been a key contributor in this field, having conducted multiple successful discovery campaigns targeting E3 ligases.
A privileged platform for Molecular Glue drug discovery
Screening cascade strategies for the identification of molecular glue degraders are well established. These approaches typically begin with the identification of ligands targeting the E3 ligase of interest. Libraries of such compounds are then screened for their ability to induce cooperativity with other proteins or directly assessed in degradomics assays to uncover molecular glue degraders. However, our experience indicates that cooperativity is not necessarily correlated with ligand affinity for the binary complex. This highlights a critical need for new methodologies that enable the direct identification of molecular glues through systematic screening of protein pairs. Such strategies would not only accelerate discovery but also yield deeper mechanistic insights into glue-induced complex formation, ultimately enabling more rational and scalable molecular glue development. In this context, Edelris has developed a differential AS-MS platform designed to identify compounds that preferentially stabilize ternary complex formation over binary interactions.
Differential AS-MS
Differential AS-MS relies on comparing mass spectrometry results from independent screens of individual proteins versus the protein pair to identify cooperativity. In this method, screens are run on Target A alone, Target B alone, and the mixture of A + B. The goal is to identify compounds (Molecular Glues) that bind in when both proteins A and B are present, through the formation of a ternary complex, but not (or less strongly) to the individual proteins. It may also detect cryptic site binders exposed by conformational changes.
Key strengths: It is a quick and robust assay using high-throughput automated SEC-based methods (SpeedScreen or ALIS).
Limitations: It has higher protein consumption than other methods and may identify unwanted cryptic binders due to conformational changes in the ternary complex.
Immobilized AS-MS
Immobilized AS-MS uses physical immobilization of one protein to capture the complex. In this approach, Protein A is immobilized (e.g., on resin or Magbeads). Protein B and the compound library are added. Cooperativity strengthens the complex stability, allowing it to survive washing steps before denaturation and analysis.
Key strengths: It effectively enriches for true stabilizers of ternary complexes and is high-throughput.
Limitations: It requires one tagged protein, and the conditions of the washing step are critical to success (potentially risking the loss of weaker interactions).
Hybrid Strategy
Using a Hybrid Strategy: Interaction method (e.g. LUMIT) + AS-MS involves combining a proximity-based bioluminescence assay with mass spectrometry deconvolution. The initial screening is performed using a proximity assay (for example, LUMIT, providing tagged proteins are available) to detect ternary complex formation in pools of compounds. AS-MS is then used specifically for hit identification/deconvolution.
Key strengths: It offers low protein consumption and detects ternary complexes directly via the proximity assay. It requires a smaller number of pools for the AS-MS screening step.
Limitations: It requires antibodies recognizing proteins (or their tags) and assay development is more extensive.
Up until now, many molecular glues have been discovered through sheer serendipity. Through smarter chemistry linked closely to our adaptable and robust ASMS screening platform, the team at Edelris are working with our partners to introduce a more rational roadmap for induced-proximity drug discovery.
Contact us today to explore how our molecular glue screening platform can advance your next breakthrough!
Traditional occupancy-based pharmacology typically works by simply inhibiting a target protein. In contrast, proximity-induced drug discovery represents a paradigm shift where small molecules are designed to bring proteins into close proximity to enforce protein–protein interactions. This mechanism allows for new biological outcomes, such as recruiting cellular degradation machinery to eliminate disease-relevant proteins or stabilizing interactions to modulate activity without causing protein loss.
PROTACs (proteolysis-targeting chimeras) are heterobifunctional molecules consisting of three parts: a ligand for the target, a ligand for an E3 ligase, and a chemical linker connecting them. They work by simultaneously engaging both proteins to form a ternary complex. Conversely, molecular glue degraders are typically monovalent, low-molecular-weight compounds that do not physically link two binding moieties. Instead, they reshape the surface of a protein (often the E3 ligase) to create a complementary interface that recruits the target protein for ubiquitination.
Yes. Non-degrading molecular glues function by stabilizing or inducing protein–protein interactions without engaging the ubiquitin–proteasome system. By bringing a protein into proximity with a binding partner, these molecules can reprogram protein behaviour, leading to changes in localization, complex formation, or downstream signalling. This offers reversible and tuneable control over biological processes, which is particularly valuable for regulating transcription factors and signalling adaptors.
While early TPD strategies relied on a few well-characterized E3 ligases like CRBN and VHL, the human genome encodes over 600 E3 ligases, most of which are untapped. Identifying novel E3 ligase ligands allows drug developers to tailor proximity-based mechanisms with greater control over tissue selectivity, degradation kinetics, and target scope. Engaging ligases with distinct expression patterns and subcellular localizations unlocks the full potential of targeted protein degradation.
Standard screening methods often assume that cooperativity correlates with ligand affinity for a binary complex, which is not always the case. To address this, Edelris developed a differential AS-MS (Affinity Selection-Mass Spectrometry) platform designed to directly identify compounds that preferentially stabilize the ternary complex over binary interactions. This strategy accelerates discovery and yields deeper mechanistic insights into glue-induced complex formation, enabling more rational development of molecular glues.
Edelris utilizes a dedicated platform that combines powerful AS-MS screening technologies with expertise in sp3-rich, 3-dimensional natural product-inspired chemistry and high-throughput synthesis. We have developed E3-ligase biased libraries and explored our proprietary Keymical Space to create novel, patentable degraders. For example, using a virtual CELMoD-library of 30,000 compounds, we successfully identified new small-molecule binders for CRBN that serve as strong starting points for molecular glue degrader library expansion or as warheads on PROTACs.
The hybrid strategy combines LUMIT, a proximity-based bioluminescence assay, with AS-MS deconvolution. In this workflow, tagged proteins are used to detect ternary complex formation via the LUMIT proximity assay in pools of compounds. Hits are then deconvoluted and identified using AS-MS. This method is advantageous because it consumes low amounts of protein and allows for the direct detection of ternary complexes.