Molecular Glues Meet Precision Discovery To Advance Oncology Treatments
Molecular glue degraders are redefining cancer treatment by targeting proteins once considered undruggable
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The pharmaceutical landscape is undergoing a transformative shift with the emergence of novel therapeutic modalities aimed at overcoming one of drug discovery’s most enduring challenges: the so-called "undruggable" proteome. Conventional small-molecule inhibitors often fail against targets lacking well-defined active sites, such as transcription factors, scaffold proteins or components of multiprotein complexes. To address this gap, researchers are increasingly turning to targeted protein degradation strategies, including the use of proteolysis targeting chimeras (PROTACs) and molecular glues.
Molecular glues represent a compelling opportunity to reframe druggability, particularly given their catalytic mode of action and ability to modulate previously inaccessible targets. However, their discovery has largely been serendipitous, with few systematic frameworks available to identify or design glue molecules rationally de novo. This has posed a major bottleneck in expanding the chemical space of molecular glues and applying them to a broader swath of disease-relevant proteins.
We spoke to Dr. Christian Dillon, chief scientific officer at PhoreMost, at the American Association of Cancer Research (AACR) Annual Meeting 2025 whose team has developed GlueSEEKER – a computational-experimental platform designed to identify new molecular glue degraders systematically. We explored how molecular glues differ to PROTACs, where the field currently stands in clinical progression, remaining challenges to overcome and how GlueSEEKER is helping to advance the therapeutic landscape in oncology and beyond.
For readers that may be unfamiliar, can you tell us what molecular glues are and how they differ from other targeted protein degradation approaches like PROTACs?
Christian Dillon, PhD (CD):
Molecular glue degraders (MGDs) are an emerging class of small molecule drugs that exploit the cell’s protein degradation machinery by inducing close proximity between a target and an effector protein. The MGD stabilizes interactions between the effector protein, typically an E3 ligase, and the target thereby “gluing” them together. The net result is the formation of a ternary complex that drives the ubiquitination and subsequent degradation of the target protein. More broadly, molecular glues are also being developed that can recruit other types of effector or chaperone proteins to targets, leading to either gain-of-function or loss-of-function outcomes with therapeutic potential.
Unlike PROTACs and other bivalent molecules, MGDs are monovalent – meaning they are typically much smaller molecules with more drug-like properties. This can allow for easier absorption and more favourable ADME (absorption, distribution, metabolism and excretion) and pharmacokinetic properties.
KS:
Where does the field of molecular glues currently stand in terms of discovery and application? Are any MGDs approaching the clinic, and what are some of the key challenges that remain?
CD:
The field has progressed significantly in recent years and is already a clinically validated modality with the United States Food and Drug Administration (U.S. FDA) approval of the immunomodulatory imide drugs: thalidomide, pomalidomide and lenalidomide. These drugs act through the effector E3 ligase, Cereblon, and result in the degradation of a defined set of targets – many of which were previously deemed “undruggable” transcription factors. Newer MGDs are also progressing through clinical evaluation in a range of cancers as well as in immune-related diseases. As of November 2024, there were 17 MGDs undergoing clinical trials with this number set to increase as more mechanisms and targets are uncovered. We are also seeing more and more partnerships between pharmaceutical companies and degradation-focused biotech companies, highlighting the strong and growing interest in the field and reflecting its potential to drug high value, disease-relevant targets that have proven elusive to traditional discovery paradigms. Such partnerships either seek to develop newly discovered MGDs or utilize a diverse range of platform technologies for the identification of MGDs.
The potential for this modality is clear, but some significant challenges within the field remain. A major challenge is that the majority of MGDs identified to date have either been discovered serendipitously or by testing structural variants of known molecular glue compounds, highlighting the need to develop new methods or platform technologies that can aid their rational discovery. Further, despite recent progress, the diversity of degrading mechanisms and the range of targets for which MGDs have been discovered remains relatively restricted. For example, most known MGDs exploit just a single effector E3 ligase, Cereblon. This is of course both a current limitation within the field but also a huge opportunity for innovative approaches to impact the next generation of MGD therapies.
KS:
How can GlueSEEKER help?
CD:
KS:
You presented a poster at AACR 2025 entitled “Systematic identification and translation of novel targeted protein degradation mechanisms”, can you talk us through the research?
CD:
KS:
How is PhoreMost using GlueSEEKER to progress its own pipeline of assets?
CD:
PhoreMost is progressing a pipeline of both monovalent molecular glue degraders and bifunctional degrader molecules that function via differentiated E3 ligase mechanisms. We are using GlueSEEKER to help identify and enable novel MGD discovery across a range of oncology applications, with a specific focus on enabling novel E3 ligases that have so far not been utilised for MGD discovery. We believe there is a tremendous opportunity in this exciting area.
