You may have heard of molecular glue degraders; dubbed nature’s matchmakers, these are small molecules that help ‘glue’ proteins to each other, one being a rogue protein previously regarded as undruggable. Traditional proximity medicines are aimed at drugging these undruggable targets, but new proximity medicines are on the way to make this process more efficient as novel ways to discover targets are explored.
The typical molecular glue degrader acts as a double-sided tape. It helps bind an enzyme called E3 ubiquitin ligase, whose job is to tag damaged proteins and destroy them, and the destructive protein to each other.
“Degraders are the most advanced induced proximity modality. By stabilizing weak interactions between a target protein and a ubiquitin ligase, these small molecules can trigger the rapid and profound elimination of the target by the proteasome,” said Matthias Brand, chief technology officer of Vienna-based Proxygen, a company developing next-generation proximity medicines.
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How are molecular glues different from other degrader drugs?
Molecular glue degraders are not to be confused with proteolysis targeting chimeras (PROTACS), which also destroy disease-causing proteins, but instead of ‘gluing’ proteins together, they consist of a chemical linker and two ligands that binds the target protein and the E3 ligase. The first-ever PROTAC, Arvinas and Pfizer’s oestrogen receptor degrader vepdegestrant and branded Veppanu, was greenlit to treat patients with advanced breast cancer by the U.S. Food and Drug Administration (FDA).
Molecular glues, on the other hand, don’t have a linker to bind proteins to one another. Plus, they are much smaller than PROTACs and are effective in crossing the blood brain barrier.
The glue often binds to E3 ubiquitin ligase, which fits into a specific pocket on the protein’s surface. When this happens, the glue mildly changes the shape of the enzyme so that a sticky zone is created on the enzyme to trap the target protein, and then forms what is known as a ternary complex. This complex activates the E3 ligase enzyme and it attaches a tag called ubiquitin onto the damaged protein. Ubiquitin essentially labels the protein as trash, which the proteosome – that act as the garbage recycling system in cells – recognizes, breaking it down to amino acids that are harmless. With this, the molecular glue detaches and repeats the process to degrade another protein.
Glue degraders have made quite the splash with big pharma investing heavily in the field. AbbVie’s $1.64 billion deal with Neomorph to create glues for immunology and cancer targets was signed last year. This was following Neomorph’s $1.45 billion and $1.46 billion pacts with Lilly and Biogen, respectively, in 2024.
Moreover, Massachusetts-based Magnet Biomedicine forged a $1.25 billion agreement to drug difficult-to-drug cancer targets last year, Novartis and Monte Rosa Therapeutic penned a $5.7 billion deal for the giant to license an undisclosed discovery target, Massachusetts-based Orionis Biosciences also struck a $2 billion deal with Genetech, and Takeda signed a $1.2 billion licensing deal with Shanghai-based Degron Therapeutics to advance degraders for oncology, neuroscience, and inflammation, all in the past two years.
Proxygen’s next-generation molecular glues eliminate disease-causing proteins
Brand’s Proxygen also cut a deal with American giant Merck for $2.55 billion to identify and develop molecular glue degraders against multiple therapeutic targets back in 2023, making this its third big pharma partnership following ones with Germany’s Merck and Boehringer Ingelheim.
However, Proxygen’s approach to discovering proximity medicines varies from traditional glues. While many traditional molecular glues like lenalidomide were discovered serendipitously, the Viennese biotech’s platform conducts large-scale screening of glues targeted towards specific proteins that drive disease. Brand explained that it has specialized in identifying which of the about 600 cellular ligases are best suited for a target of interest and then finding the right molecules to glue them together.
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“So many more processes in the cell beyond degradation are mediated by interactions between proteins, and can therefore be reprogrammed with small molecules,” said Brand.
What if we reprogram a protein of interest to do completely new functions, he asks?
“One could activate or deactivate specific transcriptional programs by relocalizing transcription factors specifically, create connections between different signaling pathways, change the subcellular localization of proteins and much more. At Proxygen, we are now putting our technology to use to tackle unmet medical by creating new interactions for target proteins to either degrade them or reprogram their biology in novel ways,” said Brand.
The company’s next generation proximity medicines utilize different mechanisms. From rewiring transcription in a targeted manner by recruiting transcription factors or transcriptional regulators to proteins localized at specific sites of the genome, to changing the function of mutant oncogenes to actively induce cell death in the cancer cells, thereby circumventing resistance mechanisms that reactivate their oncogenic signaling, there’s a lot in play, Brand described.
“And, of course, we have multiple degrader programs in development which utilize novel ubiquitin ligases that we select based on their intrinsic affinity for the target of interest,” he added.
Its lead candidates came out of this platform: p300 and CDK12 are expected to enter investigational new drug (IND)-enabling studies next year.
“Our p300 program has a unique covalent pharmacology which has the potential to deliver more profound efficacy while allowing safe combination in clinical practice through low and infrequent dosing schedules; and our CDK12 program exploits the favorable chemical features of glue degraders to achieve impressive brain penetrance and provides novel treatment options for patients with brain metastases, who are often underserved,” said Brand.
A central feature of the p300 program is the covalent programming of the recruited E3 ligase. The degrader mechanism acts catalytically, enabling durable target degradation even after compound exposure declines, according to the company. p300 degradation suppresses oncogenic transcriptional programs and has demonstrated robust anti-tumor activity in preclinical models.
As for the CDK12 program, the goal is to eliminate cyclin K, a protein that is frequently overexpressed in cancers. Doing so disrupts CDK12-dependent transcriptional programs required for tumor cell survival while maintaining high selectivity across the broader CDK family. Proximity molecules work hard to address cancer and neurological conditions, Brand pointed out.
“Both cancer and neurological disorders are caused by aberrant protein function, mislocalization, toxic gain-of-function biology, or dysregulated cellular programs that unfold over long periods of time. Progress on some of the most promising targets causing the disease has been limited since they are considered undruggable – for example, they lack the deep binding pockets that are required for inhibitors, are highly conserved so selectivity becomes a significant challenge for the chemistry, or they are intracellular and therefore out of reach for antibodies and biologics,” he said.
Being covalent molecular glues, they don’t rely heavily on cooperative binding, compared to monovalent ones.
“This means that a lot of the required binding energy is contributed by direct interactions between the two proteins, and the molecule orchestrates this binding without needing to have strong affinity for both of them. Thereby, even undruggable targets can be modulated by proximity-inducing drugs. Even more appealing is the variety of responses that can be achieved through them, which go beyond only blocking its activity, instead rewiring it in a way that cannot easily be compensated for by the cancer cell or that can directly restore the molecular function underlying the disease,” said Brand.
Additionally, Proxygen is putting together programs beyond degradation to reprogram target protein biology in new ways using novel induced proximity modalities. Hit-to-lead optimization studies are planned for next year.
Next-generation proximity medicines: how do RIPTACs work?
Meanwhile, Regulated Induced Proximity Targeted Chimeras (RIPTACs) are another kind of next-generation proximity medicine moving up the pipeline. Pioneered by Halda Therapeutics – owned by Johnson & Johnson since December – these glues exhibit what Halda called the “hold and kill” mechanism to destroy cancer cells.
Instead of relying on E3 ligases and the cell’s proteasome to destroy a protein, RIPTACs are molecules whose one end binds to the target protein and the other to the pan-essential protein required for cell survival, thus forming the ternary complex to degrade the problematic protein. Halda’s RIPTAC HLD-0915 hit the clinic last year and early results were encouraging.
These molecules are highly selective, akin to antibody-drug conjugates, but act as oral small molecules. In fact, there may be molecular glues that can overcome the challenges associated with ADCs, the main one being drug resistance.
Can proximity molecules overcome ADC drug resistance?
Glue DACs, developed by Massachusetts-based Fortitude Biomedicines are hoped to achieve this by swapping traditional cytotoxic payloads for molecular glue degraders.
“Resistance is increasingly emerging as a challenge in the current ADC therapeutic landscape. The field urgently needs payloads with distinct mechanisms of action. GLUE-DAC technology meets this unmet need by combining the validated delivery capabilities of antibodies with the transformative potential of targeted protein degradation,” Jin Wang, professor in Pharmacology at Baylor College of Medicine, had said in a press release.
With its Glue DAC in the discovery stage, Fortitude launched with $13 million in seed funding in 2026. Hoping to expand the therapeutic window of ADCs, the company’s president and chief executive officer (CEO) Jesse Chen called the mechanism “powerful.”
He said: “With proprietary antibody-based technology, we are unlocking the ability to precisely target diseases while engaging the body’s own biology in powerful, transformative ways.”
Similarly, California-based General Proximity is trying to speed up the discovery of drugs rooted in molecule glue mechanisms. Its OmniTAC platform scans a host of effector proteins to develop next-generation proximity medicines to address cancer, cardiometabolic disease, neurodegeneration. Investors FreeMind Investments and Daewoong Pharmaceuticals have put their faith in the platform, having spent an undisclosed amount on the startup this month.
As next-generation proximity degraders are rising to the challenge of drugging undruggable targets, it looks like how drug developers are hunting for these medicines is also changing, and possibly for the better.
