Targeting the Untouchable: How Protein Slayers are Conquering Diseases

The original Chinese version of this article was published in the June 2025 issue of Global Science (the Chinese edition of Scientific American).

In the late 1950s, a “miracle drug” swept across the world. Thalidomide, produced by the German pharmaceutical company Grünenthal, became an international bestseller in less than a year. In 46 countries across Europe, Asia, and Africa, the drug was embraced by expectant mothers. It eased morning sickness, soothed anxiety, and helped them sleep. For countless women, thalidomide promised comfort and peace during pregnancy.

But the story soon turned dark. The drug that mothers praised as a lifesaver became a catastrophe for their children. Within a few years, reports of babies born with shocking birth defects began to surge. Some infants had stunted limbs, resembling flippers. Others were born without ears. Still others suffered from lethal heart malformations or gastrointestinal defects. As epidemiologists and toxicologists dug deeper, the link between thalidomide and these devastating outcomes became undeniable. By 1961, most countries had banned its sale. Yet the damage was already done. In just four years, nearly ten thousand babies were born with severe deformities, and countless families were left shattered.

Still, the story of thalidomide did not end there. Fate had one more twist in store. While most countries outlawed the drug, it lingered in places with weaker oversight. In 1964, a physician prescribed it as a sedative to a patient with leprosy. To everyone’s surprise, the patient’s eruptions began to clear within days.

This accidental discovery reignited scientific interest in thalidomide. Researchers began to explore thalidomide’s therapeutic potential beyond pregnancy. Over time, they found that thalidomide and a new generation of related compounds, including pomalidomide and lenalidomide, could not only treat leprosy but also combat certain cancers like multiple myeloma, subsequently earning regulatory approval.

How could a single drug be a potent sedative, an anti-inflammatory agent, an anti-cancer therapy, and yet also trigger catastrophic birth defects? The paradox puzzled scientists for decades. The answer finally emerged in 2014, when two landmark papers in top journals revealed a unifying mechanism: thalidomide is a protein slayer. It works by triggering the destruction of specific proteins. In embryos, this means eliminating proteins essential for normal development, with disastrous results. In cancer cells, it means dismantling proteins that tumors depend on to survive.

Nowadays, researchers around the world are searching for more protein slayers like thalidomide. Some are even designing molecules that can deliberately target and destroy disease-causing proteins. Early clinical trials of such drugs have already produced promising results. More importantly, they signal the arrival of a new era in medicine: one in which small molecules can be engineered to precisely control life’s key mechanisms, rewriting the destinies of diseases and patients alike.

The Protein Slayers

Proteins are the foundation of cellular life. Every process within a cell depends on proteins working smoothly. Because of this, our bodies have evolved a finely tuned protein management system that carefully regulates both the quantity and quality of all proteins.

Like an industrial assembly line, it oversees every step, from production, quality control to deployment, from active use to eventual disposal. Useful proteins must be produced in large numbers and properly maintained, while redundant or harmful proteins must be swiftly cleared out.

If this delicate system goes awry, the consequences can be dire. If proteins that drive cell growth and division linger too long, they can push cells into unchecked proliferation, setting the stage for cancer. If faulty proteins pile up in the brain without being cleared away, they can trigger neurodegenerative disorders such as Alzheimer’s disease. Maintaining a dynamic balance of proteins is one of the cornerstones of our health.

Thalidomide earns its title as a protein slayer because it directly targets the cell’s primary protein-disposal pathway. At the heart of this pathway lies a massive molecular machine called the proteasome, serving as the cell’s paper shredder for proteins. Shaped like a cylindrical trash can with lids on both ends, it prowls the cellular interior, always ready to swallow up and destroy proteins that have been tagged for disposal.

This special tag is called ubiquitin, a tiny, ubiquitous protein found throughout the cell. Ubiquitin has many roles, but its most important job is to tag proteins for clearance: when a protein malfunctions or has finished its task, an enzyme called ubiquitin ligase (E3) covalently attaches one or more ubiquitin molecules to it.

A ubiquitinated protein is like a beacon in the dark, it stands out and becomes prey for the proteasome. The tagged protein is threaded into one end of the cylindrical proteasome and rapidly shredded into fragments (short peptides or even single amino acids), which are then expelled from the other end. For revealing this elegant protein degradation system, three scientists were awarded the Nobel Prize in Chemistry in 2004.

Could this disposal pathway be hijacked on purpose? Could we program ubiquitin to mark whatever protein we choose, and thus force the cell to destroy that target? That was the bold idea conceived by Craig Crews and Raymond Deshaies.

In 1998, at a conference in Washington State, Crews and Deshaies found themselves seated side by side—thanks to the alphabetical order of their surnames. At the time, Deshaies was studying how ubiquitins are attached to proteins by E3, while Crews was exploring ways to bring two different proteins into close contact. Fueled by a few beers, the two began to wonder: what if one could design a molecule that grabbed an E3 with one hand and simultaneously a chosen target protein with the other? This would force the cell to tag and destroy the protein of interest. The idea clicked instantly.

Not long afterward, they designed such a molecule. It resembled a dumbbell: one end bound to an E3, the other to the target protein. To their astonishment, the approach worked far faster than expected. Target proteins disappeared within hours or even minutes, like a sniper’s clean shot.

They named this class of molecules proteolysis targeting chimeras, or PROTACs. They hypothesized that by swapping out one end of the dumbbell, almost any protein in the cell could, in theory, be marked for elimination. In 2013, Crews founded the biotech company Arvinas to focus on developing PROTAC-based medicines.

This precise, efficient, and programmable mechanism seemed revolutionary, yet nature had long been playing a similar trick. Certain viruses, such as human papillomavirus (HPV), produce a protein called E6. E6 can bind both to an E3 and to key regulatory proteins inside the host cell. Once those regulatory proteins are destroyed, the cell loses its brakes and can spiral into uncontrolled growth and the development of cervical cancer.

Thalidomide, too, works by bringing an E3 close to a target protein. “When thalidomide binds an E3,” explains Yong Cang of ShanghaiTech University, “it reshapes the ligase to form a new binding surface, one that recognizes proteins it normally would ignore.”

Unlike PROTACs, however, thalidomide is far simpler. Instead of a dumbbell with two ends, it works more like a piece of double-sided tape, sticking two unrelated proteins together. For this reason, scientists vividly dubbed this mechanism molecular glue. Within the broader category of molecular glues, the subset that induces protein degradation are known as molecular glue degraders. As medicinal chemist Derek Lowe once marveled, “It feels like a proposal to stick watermelons together by using a couple of red grapes in between them. But there are things in biology that work that we’d never think up by ourselves.”

Flexing New Muscles

For medicinal chemists, molecules like PROTACs and thalidomide are thrilling because they dramatically expand the arena in which drug discovery can play. For decades, researchers faced a stubborn problem: scientists had identified many proteins strongly linked to disease, yet only a tiny fraction could actually be tackled by drugs.

The reason was partly technical. Conventional small-molecule drugs can only block a protein’s function; they cannot make the protein disappear altogether. Worse still, most disease-related proteins have no obvious active site or binding pocket where a small molecule could latch on. As Cang explains: “Of the disease-associated protein targets we know today, about three-quarters cannot be modulated by traditional small-molecule drugs. That is to say, they are undruggable.”

The rise of targeted protein degradation (TPD) has changed that equation. Instead of delicately inhibiting a protein’s activity, these approaches take a far more simple, brute-force approach: total annihilation. For PROTACs, the only requirement is to bring the target protein into close contact with an E3. Once that happens, the cell’s shredding machinery takes care of the rest.

“The structure of the target protein isn’t even required,” Crews notes. “As one just needs to screen molecular libraries for compounds that bind to the target. This liberates one from the limitation of having to develop molecules that target an active site.”

Compared with PROTACs, molecular glue degraders like thalidomide offer an even broader reach. PROTACs still require some kind of binding pocket on the target protein to latch onto, but not all proteins possess such a pocket. Molecular glue degraders, however, binds the E3 and reshapes its entire surface. That remodeled interface can then grab hold of proteins that would otherwise be out of reach. Once tagged with ubiquitin, those proteins too are fed into the proteasome for destruction.

Cang estimates that by targeting just one E3—CRBN, the E3 bound by thalidomide, could in principle yield molecular glue degraders for 4,000 different proteins, nearly one-fifth of all proteins in the human body. And CRBN is only one of more than 600 E3s encoded in our genome, most of which remain poorly studied. The potential for developing molecular glue degraders is therefore enormous.

Beyond sniping soluble proteins inside cells, TPD can also tackle protein aggregates, whole organelles, and even extracellular components. That is because the proteasome is not the cell’s only waste-disposal system. Long before the ubiquitin–proteasome pathway was discovered, scientists knew of another route: cells can bundle damaged organelles, misfolded protein aggregates, or even invading bacteria and delivere them to a cellular compartment called lysosome, where they would be broken down. Lysosomes can even digest material engulfed from outside the cell.

The proteasome and lysosome work in parallel, each taking on distinct cleanup jobs. The proteasome excels at rapidly degrading soluble proteins inside cells, while lysosomes can handle much larger structures, both inside and outside the cell. These bulkier targets are often beyond the reach of traditional small-molecule drugs. For instance, the amyloid aggregates that accumulate in the brains of Alzheimer’s patients cannot be directly cleared with conventional drugs, and even PROTACs cannot touch them.

To address such harmful components, scientists asked whether the lysosomal pathway could also be harnessed in a PROTAC-like fashion. Building on this idea, Nobel laureate Carolyn Bertozzi developed lysosome targeting chimeras (LYTACs), which can deliver cell-surface or extracellular proteins into lysosomes for destruction. Similarly, Hirokazu Arimoto at Tohoku University in Japan devised a similar strategy that directs lysosomes to selectively eliminate malfunctioning mitochondria.

As Longlong Si of Shenzhen Institutes of Advanced Technology reflects, “From proteasomes to lysosomes, the pieces of the targeted protein degradation puzzle are coming together, covering virtually every scale of protein structure, inside and outside the cell.”

A New Era for Small-Molecule Drugs

The rise of TPD, especially molecular glue degraders, has prompted scientists to reconsider a big question: could the way we treat disease become more affordable and accessible?

For more than a century, small-molecule drugs have been the backbone of modern medicine. They are inexpensive to manufacture and transport, can be taken orally, and allow flexible dosing. These features have long made them popular with patients and physicians. But over the past decade, the spotlight has shifted toward costly biologics such as antibodies, mRNA vaccines, and cell therapies. These high-tech treatments have dazzled the public, and in 2023 the approval of Casgevy, the first gene-editing therapy for sickle-cell disease, sent expectations for biologics soaring even higher.

Yet as Cang points out, gene therapy is not a realistic option for much of the world. It comes with staggering costs and demands extensive medical infrastructure. Sickle-cell disease affects an estimated 8 million people globally, the vast majority of them in sub-Saharan Africa, where healthcare resources are scarce. For these communities, a complex, high-cost gene therapy is unlikely to be a practical solution.

Small-molecule drugs, particularly molecular glue degraders, may offer a different path. Encouragingly, in 2024 both Bristol Myers Squibb (BMS) and Novartis have advanced candidate molecular glue degraders for sickle-cell disease into clinical trials. “These represent profoundly important, revolutionary therapies,” Cang says.

But Cang admits that developing molecular glue degraders is also challenging, because they are almost impossible to achieve through rational design. “These molecules work by stacking together numerous weak interactions that, in aggregate, reshape the entire structure of the E3,” he explains. “That is fundamentally different from traditional small-molecule drugs or even PROTACs. Chemists cannot simply design such compounds rationally.”

Indeed, most molecular glue degraders have not been invented by design but stumbled upon by chance. Thalidomide itself is the prime example: its molecular glue mechanism was only unraveled nearly 60 years after it was first used in patients. In 2022, researchers at Genentech reported in Cancer Discovery that a drug they had abandoned years earlier because of severe side effects turned out, in hindsight, to be a molecular glue degrader. A subsequent literature search revealed nearly 40 other compounds with similar properties, leading to the realization that molecular glue degraders might be far more common than previously thought.

It is possible that other clinically used drugs are quietly acting as molecular glues without being recognized. But rather than waiting for serendipity, Cang has chosen to blaze a more deliberate path. Earlier research had suggested that thalidomide, lenalidomide, and their chemical cousins could only degrade the same type of proteins. However, a landmark 2016 study published in Nature showed that by tweaking lenalidomide’s structure, chemists could create compounds capable of targeting entirely new categories of proteins. That same year, such redesigned glues entered clinical trials.

Inspired by this, Cang founded Degron Therapeutics, a company dedicated to systematically discovering new molecular glue degraders. His team has synthesized a library of compounds that can bind CRBN and reshape its surface to generate novel binding interfaces. Each new interface, Cang speculates, might attract a specific set of target proteins. Their mission, then, is to identify which proteins are drawn to which interface, and harness that interaction for therapeutic ends.

After large-scale screening and validation, Degron Therapeutics finally identified a molecular glue degrader capable of targeting human antigen R (HuR), a protein that plays key roles in cancer and other diseases. Although its mechanism resembles that of thalidomide, its structure is entirely different. In January 2025, Cang revealed, this candidate drug entered clinical trials in the U.S., marking another molecular glue degrader with potential to treat cancer.

Other scientists, meanwhile, realized that if a single small molecule can bring two enormous proteins together and alter their fate, why stop at destruction? Why not harness this powerful mechanism to trigger protection, inactivation, modification, repair, or even entirely new functions never before seen in biology? This line of thought has sparked an emerging field known as chemically induced proximity.

For example, building on the blueprint of protein slayers, researchers have begun to design protein guardians. Many proteins are degraded only after being tagged with “ubiquitin advertisement”. If, instead of recruiting the “advertisement poster” (E3), but guiding the “advertisement cleaner” (deubiquitinase) to remove those tags, it could rescue proteins from premature destruction. Already, chemists have developed prototype molecules that protect proteins from degradation, and they are testing whether such protein guardians might treat diseases caused by aberrant protein loss, such as cystic fibrosis or certain types of cancer.

With the momentum of molecular glues and related innovations, small-molecule drug discovery is undergoing a renaissance. As early as 2015, Deshaies remarked in a commentary published in Nature Chemical Biology: “The gold rush is on!” Keith Hornberger, head of medicinal chemistry at Arvinas, is more cautious. He argues that it may be too soon to declare a “golden age,” but he agrees on one thing: we are indeed entering a new age of small-molecule therapeutics.

Encoding the Slayers

Despite all the advances, no matter what functions they achieve, whether targeting free proteins, aggregates, or even organelles, small molecules can only manipulate the local environment of the cell. Si was not satisfied with that. He wanted to go further: to move beyond the reach of degraders and instead rewrite the destiny of living organisms. Out of this vision came a novel form of live-attenuated vaccine.

Si realized that if the concept of TPD could be encoded directly into a viral genome, one could design a virus whose replication was inherently self-limiting. Once such a virus entered a cell, its key proteins would be efficiently bound by an E3 and quickly degraded. The virus could replicate normally in controlled production systems, such as a laboratory, but inside the human body its replication would be sharply curtailed, or even halted altogether. The result would be a safe live-attenuated vaccine. Such a vaccine can stimulate the immune system by mimicking a genuine infection closely enough to build strong immune memory, yet without the risk of real disease.

In a 2022 paper in Nature Biotechnology, Si’s team reported the creation of such proteolysis-targeting (PROTAR) vaccines. Further optimization was detailed in January 2025 across two papers in Nature Chemical Biology and Nature Microbiology, where they developed several PROTAR-based influenza vaccine candidates.

Si’s team engineered the influenza virus genome by introducing a small peptide that efficiently binds to a human E3 into several key viral proteins. In laboratory cell lines lacking such E3, the modified virus replicated efficiently, enabling large-scale, low-cost vaccine production. But once the virus entered normal cells or an animal host, its engineered proteins were rapidly tagged with ubiquitin and degraded. Stripped of the ability to replicate, the virus functioned only as a safe vaccine. In animal models, including mice and ferrets, the PROTAR vaccine demonstrated remarkable safety. And a single dose was enough to trigger a strong and diverse immune response, protecting the animals against various other influenza strains.

To the researchers’ surprise, PROTAR vaccines seemed to overcome one of vaccinology’s oldest trade-offs: the balance between safety and immunogenicity. Compared with infection by wild-type virus, PROTAR vaccines provided more viral fragments on the surface of infected cells, which in turn provoked broader and stronger immune reactions.

“Once the virus enters a cell, it is degraded, and the resulting fragments are presented on the cell surface, like a wanted poster for the immune system,” Si explains. “Because PROTAR viruses are so easily degraded, they provide abundant material for recognition.” In this way, the technology enhances safety while simultaneously preserving or even boosting immunogenicity.

The approach also allows fine-tuned control. By inserting more degradation elements into the viral genome, or using different types of them, scientists can accelerate viral clearance and minimize the risk of dangerous mutations restoring virulence. As Si puts it, “It’s like turning a faucet. You can control the flow, from completely shut, to a trickle, to fully open.” Looking ahead, as researchers learn more about the E3 family, it may even become possible to tailor vaccines to individuals, adjusting designs according to each person’s unique repertoire of ligases.

Today, TPD has moved well beyond theory. It is being tested in cancer, vaccines, and a range of other fields. Clinical progress is already underway.

In 2019, Arvinas advanced two candidate drugs into clinical trials, one for prostate cancer and the other for breast cancer. In March 2025, the company reported results from a phase 3 trial: in breast cancer patients carrying estrogen receptor mutations, the oral PROTAC drug vepdegestrant (ARV-471) outperformed the existing injectable therapy. The finding suggests that the first clinically approved PROTAC may be just around the corner.

Arvinas is also pursuing therapies for neurodegenerative diseases. In April 2025, the company announced results from a phase 1 trial in Parkinson’s disease, showing that a PROTAC drug could cross the blood–brain barrier and degrade a protein closely tied to the disorder. At the same time, Cang’s team is developing treatments for autoimmune conditions, while other pharmaceutical companies are extending the approach to metabolic diseases, inflammatory skin diseases, infectious diseases, and even depression.

The age of TPD is only just beginning. Some scientists are probing the vast, still uncharted landscape of more than 600 human E3s. Others are striving to craft drugs that can selectively degrade mutant proteins while sparing their normal counterparts, or that can home in on abnormal aggregates while leaving healthy proteins intact. Still others are looking beyond proteins altogether, seeking ways to extend the strategy to RNA and other biomolecules, breaking through the traditional boundaries of small-molecule medicine. Piece by piece, experiment by experiment, researchers are dismantling old limitations and rebuilding new possibilities, driven by the hope of conquering diseases once thought untreatable.