Scientists Discover New Class of Molecular Glue Degraders for Cancer Therapy

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.

Zuzanna Kozicka, as a Ph.D. student at Friedrich Miescher Institute in Basel, Switzerland, embarked on a deliberate search for these glues with her team and identified a novel class of molecular glue degraders with more than 40 chemically diverse members. Kozicka, who is now a postdoctoral fellow at the Dana Farber Cancer Institute, also took a closer look at the crystal structures of the complexes that these molecules induce to glean clues about how they carry out their matchmaking services. She is the grand prize winner in molecular medicine of the 2023 Science & SciLifeLab Prize for Young Scientists for these discoveries.

One of the ways cells dispose of unwanted proteins is through the action of enzymes called E3 ligases-;what Kozicka refers to in her winning essay as "garbage patrols"-;that mark "cellular offenders" for destruction. Researchers want to co-opt this process to target specific disease-causing proteins, and molecular glue degraders could be one of the best ways to bring together E3 ligases with these proteins.

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."

Professor Olli Kallioniemi, SciLifeLab Director

2023 Winners

Rachel Kratofil is a winner in the prize's cell and molecular biology category for her essay "Working up an appetite to promote repair." Kratofil received an undergraduate degree from the University of Victoria and a Ph.D. in immunology from the University of Calgary. She is a postdoctoral fellow at New York University Grossman School of Medicine. Her research aims to uncover how barrier tissues adapt to microbial cues in the context of injury.

Yodai Takei is a winner in the prize's genomics, proteomics and systems biology category for his essay "Imaging nuclear architecture in single cells." Takei received undergraduate and master's degrees from The University of Tokyo and a Ph.D. from the California Institute of Technology, where he is a postdoctoral scholar in the division of biology and biological engineering. His research focuses on understanding spatiotemporal regulation of chromatin organization and gene expression.

Jessica Kendall-Bar is a winner in the prize's ecology and environment category for her essay "Lessons from sleep in the deep." Kendall-Bar received undergraduate degrees from the University of California, Berkeley, and a Ph.D. in ecology and environmental biology from the University of California, Santa Cruz. She is a Schmidt AI in Science Postdoctoral Fellow at Scripps Institution of Oceanography at the University of California, San Diego. Her research investigates the resilience and precarity of ocean ecosystems through neurophysiology, signal processing and advanced data visualization.

Source:
Journal reference:

Kozicka, Z., et al. (2023) Gluing the pieces together. Science. doi.org/10.1126/science.adl4288.

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