Targeted Protein Degradation (TPD) has emerged as a promising modality in drug discovery, hijacking the body’s natural disposal systems to eliminate disease-causing proteins. While bivalent degraders like PROTACs have pioneered the field, demonstrating clinical promise, attention is increasingly turning toward a new upstart — Molecular Glue Degraders (MGDs). These smaller, simpler molecules offer advantages but also present unique discovery challenges. MGDs have the benefit of offering simpler structures and drug-like profiles. As Benedict Cross, Ph.D., CTO and Head of Platform at PhoreMost, a company specializing in novel degrader discovery, explains below, MGDs have promising pharmacokinetic properties. In the interview below, he explains the mechanistic and pharmacological rationale behind the growing interest in MGDs, and what differentiates them from earlier TPD tools like PROTACs.
Benedict Cross, Ph.D.
For pharma professionals focused on developing targeted therapies, what are the core advantages of molecular glue degraders (MGDs) that make them promising compared to bivalent degraders?
Benedict Cross, Ph.D.: Bivalent degraders, such as PROTACs, are unusually large molecules with complex pharmacokinetics and challenging medicinal chemistry, making their bioavailability and formulation difficult. In contrast, MGDs are smaller and more drug-like, facilitating easy absorption and distribution throughout the body. Their size and structure give them better oral bioavailability, improved tissue penetration, and overall, more favorable ADME properties.
Unlike PROTACs, which require precise linker engineering to recruit an E3 ligase to a target protein, MGDs function by stabilizing new protein-protein interactions between an E3 ligase and a neosubstrate, enabling selective degradation. This mechanism allows MGDs to degrade previously undruggable targets, and makes them less susceptible to resistance mutations.
Mechanism of Targeted Protein Degradation (TPD): A small molecule brings the E3 ubiquitin ligase (purple) into proximity with a disease-associated protein target (blue), leading to poly-ubiquitylation (pink) and subsequent degradation by the proteasome (green). This process enables selective removal of pathogenic proteins.
Can you say more about why the development of molecular glue degraders represents a step forward in the treatment landscape?
Cross: MGDs represent a significant advancement in targeted therapy by addressing the limitations of existing approaches such as bivalent degraders, small molecule inhibitors, and monoclonal antibodies.
Many disease-associated proteins, including transcription factors and scaffolding proteins, lack ligand binding pockets, making them undruggable by conventional methods. MGDs overcome this by inducing novel protein-protein interactions, enabling the selective degradation of previously inaccessible targets.
In oncology, MGDs have the potential to transform treatment by degrading undruggable oncogenic drivers and overcoming emerging resistance mechanisms. This targeted approach for cancer-specific degradation can also reduce the severe side effects associated with current treatments, improving patient outcomes.
Beyond their expanded therapeutic reach, MGDs also offer practical advantages for patients undergoing treatment. Unlike inhibitors, which require continuous high dosing and are prone to resistance, MGDs work catalytically, meaning even low doses can result in sustained target depletion. This could lead to fewer side effects, reduced dosing frequency, and a lower likelihood of resistance. Additionally, MGDs can be administered orally, improving accessibility and patient adherence.
Through high-throughput effector protein engineering and screening, new enzyme surfaces are generated that induce de novo protein-protein interactions. These interactions create novel, druggable pockets that can be selectively targeted by small molecules.
What are the major hurdles in MGD development and how are those being addressed?
Cross: In the past, MGDs have been discovered serendipitously, with principles for design remaining unclear. Newer approaches that combine computational and AI methods with molecular biology offer solutions to address these hurdles by providing a high-throughput and systematic way to identify induced degradation events for almost any nominated neosubstrate and ligase pair.
The GlueSEEKER platform, for example, uses vast insertional libraries to make a massive diversity of surface-edited E3 ligase variants, followed by phenotypic screening to identify mechanisms of molecular glue activity, enabling the discovery of novel MGDs.
Beyond cancer, what is the potential scope of MGDs in treating other diseases?
Cross: An exciting prospect for MGDs lies in treating neurodegenerative diseases and brain cancers. Unlike PROTACs, which are often large and polar due to their bifunctional nature, MGDs resemble traditional small molecules, allowing for better permeability and passive diffusion across the blood-brain barrier, making them better suited for CNS-targeting therapies. This makes promising candidates for neurological diseases, where conventional therapies have struggled to deliver effective treatments.
Additionally, MGDs offer advantages for chronic conditions requiring long-term treatment. By inducing degradation through new protein-protein interactions rather than blocking active sites, they are less susceptible to resistance mutations compared to traditional inhibitors.
MGDs are smaller, simpler than PROTACs. From a drug development and manufacturing perspective, what are the practical implications of these characteristics?
Cross: Due to their small size, MGDs are easier to optimize for drug properties such as solubility and stability, making formulation simpler, and allowing for rapid iterations of the discovery process.
Moreover, because they resemble traditional small molecules, MGDs are easier to synthesize and manufacture on an industrial scale compared to larger, more complex molecules. This simplicity reduces the challenges associated with production and quality control, ultimately positioning MGDs as a more practical alternative for TPD. Over time, these factors could lead to more accessible, cost-effective therapies for patients, with fewer manufacturing hurdles and potentially lower production costs.
About the author
Benedict Cross, Ph.D. CTO, PhoreMost is the CTO and head of platform at PhoreMost, a pre-clinical drug discovery company based in Cambridge, UK. He is a geneticist & biotechnologist and has pioneered the use of computationally engineered mini-proteins to enable new medicine development, included degrader-based drugs. Ben has research expertise in proteostasis, functional genomics and chemical genetic screening and has authored over 30 peer reviewed studies and patents working at the intersection of biology, drug discovery and data science.
Filed Under: Biotech, Drug Discovery, Neurological Disease, Oncology
