The Rise of Molecular Glues in Targeted Protein Degradation: From Concept to Clinic

Targeted Protein Degradation (TPD)

In the vast landscape of modern drug discovery, an exciting paradigm shift is underway: moving beyond merely inhibiting protein function towards actively degrading disease-driving proteins. This innovative strategy, known as Targeted Protein Degradation (TPD), is reshaping the boundaries of therapeutic possibilities in unprecedented ways. For decades, many key proteins implicated in human diseases have been deemed “undruggable” because they lack the well-defined binding pockets required by conventional small-molecule inhibitors. However, TPD cleverly harnesses the cell’s own highly efficient ubiquitin-proteasome system (UPS) to precisely identify and eliminate these pathogenic proteins.

Key Advantages of TPD:

·       Catalytic Efficiency: A single degrader molecule can trigger the degradation of multiple target protein molecules, enabling potent therapeutic effects at remarkably low doses.

·       Complete Functional Removal: Unlike traditional inhibitors that merely block the active site of a protein, TPD eradicates the entire protein, thereby disabling all of its functions. This unique feature makes TPD a powerful tool against drug resistance and complex diseases.

As targeted protein degradation continues to reshape drug discovery, a unique and powerful class of small molecules has come into the spotlight: molecular glues.

Molecular Glues: A Unique Strategy in TPD

Among the different TPD strategies, molecular glues stand out for their simplicity and elegance in achieving powerful biological outcomes. Essentially, molecular glues are monovalent small molecules that directly alter cellular recognition. Unlike traditional drugs that directly block a protein’s function, molecular glues act as a molecular matchmaker. They bind to one protein – mostly commonly an E3 ubiquitin ligase, a key component of the cell’s natural protein degradation machinery – and subtly remodel its surface or induce a conformational shift. This subtle change creates a novel binding interface, allowing the E3 ligase to recognize and tightly bind a previously unassociated disease-relevant target protein (neosubstrate). This induced proximity results in the formation of a stable ternary complex (E3 ligase + molecular glue + target protein). Once glued together, the E3 ligase efficiently attaches ubiquitin chains – the cell’s “degradation tags” – to the target protein, marking it for rapid and complete destruction by the proteasome. This elegant mechanism allows molecular glues to tackle “undruggable” targets by hijacking the cell’s own quality control system, opening up entirely new therapeutic possibilities.

Molecular Glues vs. PROTACs

While PROTACs (Proteolysis-Targeting Chimeras) are the more familiar TPD modality, molecular glues exhibit distinct and complementary characteristics. PROTACs are typically bivalent molecules, functioning like a molecular “bridge” with one end binding the target protein and the other engaging an E3 ligase, connected by a chemical linker. Molecular glues, however, operate through a more subtle and indirect mechanism: they usually bind to only one protein – often the E3 ligase - and induce a conformational change or create a new binding interface on its surface. This allows the target protein, which would not normally interact with the ligase, to be recruited into a stable ternary complex.

A significant advantage of molecular glues is their generally smaller size. This often means they more easily adhere to Lipinski’s rule of five for drug conformity, enhancing the probability of good oral bioavailability. Being smaller also suggests higher membrane permeability and better cellular uptake, making them less likely than PROTACs to face major challenges in penetrating the blood-brain barrier, a critical factor for treating central nervous system (CNS) disorders. Beyond direct degradation, small molecule glues can also reprogram the binding partners of scaffolding proteins or enhance the endogenous interaction between two proteins. On the flip side, an important advantage of PROTACs lies in their versatility. Their modular design allows for rapid connection of one enzyme with many targets, making them relatively easy to design with predictable target proteins. Despite these differences, both fields are continuously evolving and show a trend towards convergence, collectively pushing the boundaries of protein degradation.  

Approved Molecular Glues: Pioneering Achievements

As of now, the FDA has approved only three molecular glue drugs: thalidomide (Thalomid®) and its analogs, lenalidomide (Revlimid®), and pomalidomide (Pomalyst®).

Thalidomide: Originally approved in Germany in 1956 and later marketed in over 50 countries, thalidomide was withdrawn in 1962 due to its tragic association with birth defects. Decades of research uncovered its anti-inflammatory and immunomodulatory properties, leading to FDA approvals in 1998 for erythema nodosum leprosum and in 2006 for multiple myeloma. Thalidomide remains in use today for several indications, with annual U.S. sales exceeding $200 million.

Lenalidomide: A second-generation derivative of thalidomide, lenalidomide offers improved efficacy with reduced teratogenicity and toxicity. Approved by the FDA and EMA in 2005 for multiple myeloma and myelodysplastic syndromes, lenalidomide has become a cornerstone therapy in hematologic malignancies, known for both its direct anti-tumor effects and immune modulation.

Pomalidomide: Approved by the FDA in 2013 and EMA the same year, pomalidomide is a third-generation immunomodulator designed for relapsed or refractory multiple myeloma, especially in patients no longer responsive to lenalidomide. It offers greater potency at lower doses with fewer side effects, further advancing the therapeutic potential of cereblon-binding molecular glues.

Molecular Glues in Clinical Development: The Road Ahead

While thalidomide and its analogs have paved the way, the field of molecular glues is far from settled. Beyond these pioneering approvals, a robust pipeline of novel molecular glue candidates is now advancing through various stages of clinical trials. This flourishing research reflects a significant push to explore the full therapeutic potential of this innovative drug modality.

Currently, over 15 distinct molecular glue compounds are undergoing clinical evaluation. These investigational drugs are designed to target a broader range of disease-driving proteins than ever before. While hematological cancers like multiple myeloma and lymphomas remain a strong focus, with key targets such as IKZF1/3 and GSPT1 under investigation, the scope is rapidly expanding. Molecules are now aiming at targets like RBM39 in acute myeloid leukemia and myelodysplastic syndromes, and even innovative targets such as PDE3A-SLFN12 in solid tumors, demonstrating a growing interest in diverse mechanisms of action.

This diverse portfolio of clinical candidates underscores a critical evolution: the move from serendipitous discovery to more rational design. Researchers are actively working to harness and expand the “molecular glue” concept beyond the well-established cereblon E3 ligase, leveraging other ligases to tackle a wider array of previously “undruggable” proteins. The ongoing clinical trials represent a hopeful future, promising to unlock new therapeutic avenues for patients facing challenging conditions across oncology, inflammatory, autoimmune diseases.