Molecular Glue Degraders Could Target “Undruggable” Proteins

Cells contain molecular machinery that targets and disposes of unwanted proteins and keeps the cell functioning normally. Scientists would like to hijack this process to control proteins involved in cancer and other diseases, using a type of molecule called a molecular glue degrader that acts as a matchmaker between target protein and the disposal machinery.

But only a few of these glue degraders have been discovered so far — mostly by chance. To remedy this, Zuzanna Kozicka, a Ph.D. student at Friedrich Miescher Institute in Basel, Switzerland, embarked on a deliberate search for these glues with her team. She has now identified a new class of molecular glue degraders with more than 40 chemically diverse members.

For this discovery, Kozicka is the grand prize winner in molecular medicine of the 2023 Science & SciLifeLab Prize for Young Scientists.

"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 both to harness existing small molecule glues and to design new ones."

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. Molecular glue degraders could be one of the best ways to bring together E3 ligases with specific disease-causing proteins.

There are more traditional methods for inactivating disease-causing proteins, by blocking or altering the active sites where their natural molecular partners bind, for example. But not all proteins have functions that can be blocked in this way, which makes them very hard to modulate with conventional drugs.

"This is why hijacking the degradation machinery to degrade an offender of interest is such an exciting strategy," writes Kozicka, now a postdoctoral fellow at the Dana Farber Cancer Institute. "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 … 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 scientists have also mapped out the structures of molecular complexes induced by many of these glues, which helps them determine exactly how they interact with ligases and offenders to bring them together.

These findings offer hints on how glues could be rationally tweaked and designed, said Kozicka. "The challenge now is to take this further, to 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. While we're not there just yet, researchers in the field are moving full steam ahead to make this a reality."

"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," said SciLifeLab Director Olli Kallioniemi. "For example, Zuzanna Kozicka's work on molecular glue degraders is reflecting innovative scientific discovery. 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."

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