In spite of immense efforts to improve conventional pharmacology methods, over three-quarters of all human proteins still remain beyond the reach of therapeutic advancement.
First author Cristina Mayor-Ruiz and last author Georg Winter. Image Credit: Laura Alvarez/CeMM.
Targeted protein degradation, or TPD, is an innovative method that could resolve this and other restrictions, and is thus a potential therapeutic approach.
TPD is built on tiny molecules, often known as “degraders,” which are capable of removing disease-causing proteins by destabilizing them.
Mechanically, the cellular protein quality control system is repurposed by these degrader drugs, which adjust this system to detect and remove harmful proteins.
To be more explicit, the degrader drugs re-direct the protein family members, that is, E3 ubiquitin ligases (E3s), towards the disease-promoting target protein. This eventually results in a “molecular earmarking” of the dangerous protein through a process known as “ubiquitination.”
Later, the ubiquitinated protein is detected and decomposed by the proteasome, a molecular machine that acts as the cellular garbage disposal system.
In this research, scientists from the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM) focused on a subset of degraders known as “molecular glue degraders”. This group of apparently rare and tiny molecules has been demonstrated to cause the degradation of target proteins that could not be inhibited through conventional pharmacology methods. As a result, such proteins had been dubbed “undruggable.”
The clinically approved thalidomide analogs are the best characterized examples and are effective for treating different types of blood cancers.
Regrettably, the finding of the few described molecular glue degraders has traditionally been a procedure that is fully driven by serendipity and no practical discovery methods had existed.
To resolve this constraint, Georg Winter’s team from CeMM endeavored to develop a scalable method for the discovery of new molecular glue degraders through phenotypic chemical screening.
As such, Cristina Mayor-Ruiz, the study’s first author and CeMM postdoctoral fellow, and her collaborators designed cellular systems that are extensively damaged in E3 activity. Differential viability between E3-proficient cells and these cellular systems was employed to detect compounds that rely on active E3s, and thus, promising molecular glue degraders.
The team combined functional genomics with drug-interaction strategies and proteomics to define the most potential compounds. They verified the method by identifying a novel RBM39 molecular glue degrader, which is structurally analogous to others described before.
Most significantly, the researchers identified a set of novel molecular glues that cause the degradation of the protein called cyclin K, which is known to play a crucial role in different types of cancers.
Fascinatingly, the new cyclin K degraders work through an unparalleled molecular mechanism of action involving the E3 CUL4B:DDB1, which has not been therapeutically investigated, to date.
Conducted in close association with CeMM PI Stefan Kubicek, the study thus offers the first framework for discovering molecular glue degraders that can be extremely scaled, but can also be robustly diversified.
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.”
Georg Winter, Study Last Author and Principal Investigator, CeMM
Mayor-Ruiz, C., et al. (2020) Rational discovery of molecular glue degraders via scalable chemical profiling. Nature Chemical Biology. doi.org/10.1038/s41589-020-0594-x.