There are many drugs on the market that target specific proteins. As many of them are implicated in a range of disease indications, it’s a great way to treat a condition head-on. Adding to this canon is a new class of therapeutic that’s currently growing in popularity: the protein degrader. These degrader drugs exploit E3 ubiquitin ligases, enzymes that play a vital role in regulating cellular proteostasis by attaching ubiquitin to target proteins, marking them for destruction.
E3 ligases are part of the ubiquitin-proteasome system, which regulates degradation in eukaryotic cells. With a number of biotech and pharmaceutical companies now investing in this field as a promising new way to eliminate toxic or disease-associated targets, there is no better time to explore the potential of protein degraders in a range of complex diseases.
To find out more about protein degraders and how GlueSEEKER — which uses computationally designed intramolecular libraries to create a vast range of surface-edited E3 ligases — can support their development, Manufacturing Chemist caught up with Dr Benedict Cross, PhoreMost’s Chief Technology Officer.
Overcoming hurdles
According to Benedict, one of the main challenges associated with degrader drug development is identifying an adequate ligand for the E3 ligase: “It can be very challenging to select the appropriate enzyme for ligand discovery and development as there are more than 600 of these in cells that could be exploited.” 
Solutions have been developed to assist this process, but Benedict states that “most high-throughput technologies in this area only operate at the in vitro level” and are “subject to protein quality challenges and phenotypic translation.” Another significant issue in the field is the over-reliance on a small handful of ligases, such as Cereblon and VHL. “There’s a great need for better, unbiased methods to enable the approach,” he adds.
A better protein degrader
Monovalent degraders, or molecular glue degraders, have seen an uptick in popularity in recent years as they exhibit their therapeutic effect by enhancing the affinity between proteins, similar to bivalent degraders such as PROTACs, but with fewer medicinal chemistry challenges due to their lower molecular weight. This results in novel interactions or the stabilisation of a molecular complex but, when it comes to the discovery and development process, there are challenges to address.
GlueSEEKER addresses this by utilising high-throughput protein-edited effector proteins such as E3 ligases to rapidly identify novel and productive protein-protein interactions. It’s able to recognise induced degradation events for almost any nominated neosubtrate and ligase pair — expanding the scope of this important modality. Phenotypic screening is then deployed to locate specific sites and precise changes, resulting in induced degradation activity, integrating deep computational approaches with novel biological discovery. The amalgamation of this approach with AI-based drug discovery presents a unique way to capitalise on improvements made in recent years.
Benedict explains: “We can explore the induced association of any effector protein and therapeutic target pair in the complex physiological environment of the cell with phenotypic measurements. By combining the novel generated data (unique biological maps) with the latest computational drug design and discovery approaches, we can create molecular blueprints for monovalent degrader design.”
“Given that other approaches are unable to address the full promise of monovalent degraders in a systematic, biologically relevant way, using GlueSEEKER means we can identify the most potent degradation route for any given therapeutic target and provide the key molecular insights to enable drug discovery,” says Benedict.
“These key molecular insights could create new drug development opportunities by maximising the potential of the known E3 ligases or it can enable completely new or unprecedented ones as they enter the drug development pipeline.”