Science & SciLifeLab Prize for Young Scientists: New molecular glue degraders could help target troublesome proteins

Cells contain molecular machinery that targets and disposes of unwanted proteins to maintain homeostasis. Scientists think that with the help of “matchmaker” molecules called molecular glue degraders, this machinery could be hijacked to control proteins involved in diseases like cancer. But only a few of these glue degraders have been discovered so far—and mostly by chance.

“Molecular glue degraders have the potential to target many proteins now considered undruggable, but finding them is challenging,” said Science Executive Editor Valda Vinson. “The judges were impressed that Zuzanna creatively combined bioinformatics, cell biology, biophysics and structural biology to not only identify more than 40 molecular glue degraders, but also provide a blueprint to both harness existing small molecule glues and to design new ones.”

There are more traditional methods for inactivating disease-causing proteins, by blocking or altering their active sites where their natural molecular partners or ligands bind, for example. But not all proteins have enzymatic functions one could block and many work as scaffolds, which makes them very hard to modulate with conventional inhibitors. “This is why hijacking the degradation machinery to degrade an offender of interest is such an exciting strategy,” Kozicka writes. “It circumvents these limitations and makes the entire target protein disappear from the cell.”

Transcription factor proteins, for instance, are high priority drug targets in many cancers, she said. “However, most transcription factors are considered undruggable by conventional small molecules due to their structural disorder and lack of discrete ligand-binding cavities.”

Glues could bridge the gap between these undruggable proteins and the cell’s garbage patrols, but until now few glue degraders have been discovered. The drug thalidomide, for instance, became infamous in the late 1950s for causing deadly birth defects and fetal limb deformities. But analogs of the drug have found new life as a treatment for multiple myeloma working via the molecular glue degrader mechanism.

To find more glue degraders, Kozicka and her colleagues analyzed databases of drug toxicity and correlated those with levels of E3 ligase activity in hundreds of cancer cell lines. They were looking for small molecules whose toxicity depended on the ligases, which would suggest they are hijacking the cellular garbage disposal process for their activity.

Their research first identified CR8, a glue degrader of cyclin K, which is a potential drug target in several cancers. Through further studies, Kozicka’s team has identified more than 40 different molecular glue degraders. The researchers have also mapped out the structures of complexes induced by many of these molecules, which helps them determine exactly how they interact with ligases and offenders to bring them together, offering hints on how glues could be rationally tweaked and designed.

“At this stage with every serendipitous discovery or molecules picked out of a systematic search like ours we are learning a lot of new things, helping us to understand the principles of molecular glue action,” said Kozicka.

“The challenge now is to take this further to make such glues prospectively designable—say, ‘oh, I want to degrade the oncogenic transcription factor Myc’ and be able to come up with libraries of chemical matter that could do that,” she added. “While we’re not there just yet, researchers in the field are moving full steam ahead to make this a reality.”

Kozicka is also curious to learn whether there are molecular glue degraders that naturally occur in our cells. “We know this is the case in plants but we have yet to discover if, for example, there are perhaps certain metabolites which induce protein-protein interactions that lead to protein degradation via this mechanism in humans,” she said.

“Receiving the SciLifeLab Prize is a great honor, and I believe it will provide me with the confidence and support to pursue more ambitious scientific questions,” Kozicka said. “I also hope that this recognition can help introduce the concept of compound-induced interactions to a wider audience, raising awareness about the potential impact of proximity-inducing small molecules.”

The Science & SciLifeLab Prize for Young Scientists acknowledges that global economic health is dependent upon a vibrant research community that needs to incentivize the best and brightest to continue in their chosen fields of research, as they begin their scientific careers.

“Every year, the Science & SciLifeLab Prize for Young Scientists brings to light groundbreaking science and exceptional young scientists who push the boundaries of our understanding. For example, Zuzanna Kozicka’s work on molecular glue degraders is reflecting innovative scientific discovery. Her systematic identification of over 40 molecular glue degraders opens a path to target disease-causing proteins. It is great for us at SciLifeLab to recognize her achievements and I believe this research will contribute significantly to the future of molecular medicine. I want to express congratulations to all the winners for their exceptional contributions and welcome them to the celebration in Stockholm in December,” said Professor Olli Kallioniemi, SciLifeLab Director.

The Science & SciLifeLab Prize for Young Scientists is made possible through generous support by Knut and Alice Wallenberg Foundation.

2023 Winners


Last updated: 2023-11-17

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