Pharma’s molecular glue garden

In the 1950s, thalidomide was introduced as a sedative and quickly became popular for treating morning sickness in pregnant women. However, its widespread use was then linked to severe birth defects in thousands of babies, prompting its withdrawal from the market in the early 1960s. 

While the tragedy significantly impacted drug regulation and safety protocols worldwide, in the decades that followed, thalidomide found a remarkable second life in medicine. 

Research uncovered its effectiveness in treating conditions like leprosy and multiple myeloma, due to its anti-inflammatory and anti-angiogenic properties, and it was discovered that the drug belonged to a special new class of therapeutics: molecular glue degraders. 

This revelation, centered around thalidomide's interaction with cereblon and other target proteins, catalyzed the exploration of similar molecules for targeted protein degradation. Since then, advances in the understanding of protein-protein interactions and the ubiquitin-proteasome system have propelled the development of new molecular glue degraders to target a variety of diseases. 

Despite their rocky origins, molecular glue degraders represent a landmark advancement in drug development, offering a novel approach to targeting and eliminating disease-causing proteins. 

These small, monovalent molecules, typically less than 500 daltons in size, operate by inducing or stabilizing protein-protein interactions (PPIs) between an E3 ligase and a target protein. This interaction forms a ternary complex that triggers protein ubiquitination (where a ubiquitin molecule attaches itself to the protein), leading to its subsequent degradation by the proteasome (the cell’s protein recycling system).

Distinguished from PROTACs (proeolysis targeting chimeras), molecular glues do not rely on bifunctional molecules linked to guide protein interaction. Instead, they work by fitting snugly between protein-protein interfaces, enhancing the affinity between an E3 ligase and a target protein to initiate degradation. 

This crucial difference in mechanism highlights the unique advantage of molecular glues, which include their smaller size, higher membrane permeability, and superior pharmacokinetic properties. These attributes not only make molecular glues highly druggable but also offer a more versatile platform for developing new treatments.

The seemingly sudden surge in interest and research surrounding molecular glue degraders can be traced back to their potent ability to target previously 'undruggable' proteins, a longstanding challenge in the pharma industry. This capability opens up new avenues for drug development, particularly in the treatment of complex diseases such as cancer, where traditional small molecule drugs and biologics have fallen short.

Currently, only thalidomide and its analogues have been approved by the FDA. But with key players entering the ring and many clinical trials underway, the molecular glue garden is bound to bloom soon. 

Teamwork   

Neomorph, Novo Nordisk 
Deal value: $1.46 billion 

Last February, Neomorph and Novo Nordisk announced a partnership aimed at creating treatments for cardiometabolic diseases and rare conditions through molecular glue degraders.  

This collaboration, valued at up to $1.46 billion, leverages Neomorph's molecular glue discovery platform and Novo Nordisk's disease management expertise. Neomorph, established in 2020, is tasked with the discovery and preclinical stages, receiving initial and potential future payments, while Novo Nordisk will oversee clinical development and commercialization.  

BMS, VantAI  
Deal value: $674 million 

Also in February, Bristol Myers Squibb and generative AI firm VantAI announced that they are partnering to discover molecular glues for therapy, leveraging VantAI’s AI for potential treatments. The deal, which could reach $674 million plus royalties, combines VantAI tech with BMS’ protein degradation expertise to create small molecule therapeutics.  

VantAI’s approach uses deep geometric learning to analyze protein interactions, aiming to streamline therapy design. This collaboration also reflects the growing interest in AI’s role in pharmaceuticals, as seen in recent deals.