Despite enormous efforts to advance traditional pharmacology approaches, more than three quarters of all human proteins remain beyond the reach of therapeutic development, according to scientists from the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna. They maintain that targeted protein degradation (TPD) is a novel approach that could overcome this and other limitations, and thus represents a promising therapeutic strategy.

TPD is based on small molecules (known as degraders), which can eliminate disease-causing proteins by causing their destabilization. Mechanistically, these degrader drugs repurpose the cellular protein quality control system, tweaking it to recognize and eliminate harmful proteins. In detail, they re-direct members of the protein family of E3 ubiquitin ligases (E3s) towards the disease-causing target protein. This leads to a “molecular earmarking” of the harmful protein via ubiquitination, says CeMM principal investigator Georg Winter, PhD, who adds that subsequently, the ubiquitinated protein is recognized and degraded by the proteasome, which serves as the cellular garbage disposal system.

Researchers in Europe, led by Winter and his CeMM team, focused on a subset of degraders called molecular glue degraders. This class of small molecules that has been shown to induce the degradation of target proteins that could not be blocked using traditional pharmacology approaches. Consequently, these proteins had been termed undruggable. The best characterized examples are the clinically approved thalidomide analogs, effective for the treatment of different blood cancers. Unfortunately, the discovery of the few described molecular glue degraders has historically been a process entirely driven by serendipity and no rational discovery strategies existed, notes Winter.

To overcome this limitation, Georg Winter’s group at CeMM set out to innovate a scalable strategy towards the discovery of novel molecular glue degraders via phenotypic chemical screening. To this end, first author and CeMM postdoctoral fellow Cristina Mayor-Ruiz, PhD, and colleagues engineered cellular systems widely impaired in E3 activity. Differential viability between these models and E3-proficient cells was used to identify compounds that depend on active E3s and were potential molecular glue degraders.

Researchers integrated functional genomics with proteomics and drug-interaction strategies, to characterize the most promising compounds. They validated the approach by discovering a new RBM39 molecular glue degrader, structurally similar to others previously described. Importantly, they discovered a set of novel molecular glues that induce the degradation of the protein cyclin K, known to be essential in many different cancer types. These novel cyclin K degraders function via a molecular mechanism of action that involves the E3 CUL4B:DDB1 and that has never been therapeutically explored before.

The researchers published their study “Rational discovery of molecular glue degraders via scalable chemical profiling” in Nature Chemical Biology.

“Targeted protein degradation is a new therapeutic modality based on drugs that destabilize proteins by inducing their proximity to E3 ubiquitin ligases. Of particular interest are molecular glues that can degrade otherwise unligandable proteins by orchestrating direct interactions between target and ligase. However, their discovery has so far been serendipitous, thus hampering broad translational efforts. Here, we describe a scalable strategy toward glue degrader discovery that is based on chemical screening in hyponeddylated cells coupled to a multi-omics target deconvolution campaign. This approach led us to identify compounds that induce ubiquitination and degradation of cyclin K by prompting an interaction of CDK12–cyclin K with a CRL4B ligase complex,” write the investigators.

“Notably, this interaction is independent of a dedicated substrate receptor, thus functionally segregating this mechanism from all described degraders. Collectively, our data outline a versatile and broadly applicable strategy to identify degraders with nonobvious mechanisms and thus empower future drug discovery efforts.”

This study provides the first framework towards the discovery of molecular glue degraders that can be highly scaled, but also strongly diversified,” says Winter.

“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,” he explains.

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