New chemical screening method could reveal molecular glue degraders

Researchers report that they have developed a scalable strategy for the discovery of novel “molecular glue degraders” via a phenotypic chemical screening. Molecular glue degraders are a class of seemingly rare small molecules that have been shown to induce the degradation of target proteins that could not be blocked via methods used in traditional pharmacology.

The study was conducted at the Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM). 

The team engineered cellular systems widely impaired during E3 ubiquitin ligase (E3) protein family activity. Differential viability between these models and E3-proficient cells was used to identify compounds that depend on active E3s and therefore potential molecular glue degraders. The researchers integrated functional genomics with proteomics and drug-interaction strategies to characterise the most promising compounds.

They validated the approach by discovering a new RBM39 molecular glue degrader, structurally similar to others previously described. They also found a set of novel molecular glues that induce the degradation of the protein cyclin K, known to be essential in many different cancer types. According to the researchers, these novel cyclin K degraders function via an unprecedented molecular mechanism of action that involves the E3 CUL4B:DDB1 and that has never been therapeutically explored before.

Cellular viability screens nominated potential molecular glues. Orthogonal investigation of the leading molecules (dCeMM1/2/3/4) enabled the characterisation of novel molecular glue degraders that recruit two different E3 ligases to induce the degradation of the proteins RBM39 and cyclin K [credit: Cristina Mayor-Ruiz/CeMM].

“I truly believe that we are only scratching the surface of possibilities. This study is chapter one of many chapters to follow. We will see a revolution in the way researchers perceive and execute therapeutic strategies for previously incurable diseases by crafting glue degrader strategies that will enable them to eliminate therapeutic targets that could not be explored with traditional pharmacologic approaches,” said last author of the study Georg Winter, of CeMM.

The results were published in Nature Chemical Biology.