Molecular glue degraders represent a novel class of small molecules in drug discovery, offering a new approach to treating various diseases. These compounds function by inducing or enhancing interactions between proteins within cells, leading to specific biological outcomes. Their unique mechanism sets them apart from traditional drugs, which typically block or inhibit protein activity. This strategy allows for precise control over protein function, opening new avenues for therapeutic interventions.
How Molecular Glues Work
Molecular glue degraders operate through targeted protein degradation (TPD), using the ubiquitin-proteasome system. This system acts as the cell’s natural recycling machinery, identifying and disposing of unwanted or damaged proteins. The mechanism involves a series of enzymes: E1 (ubiquitin-activating enzyme) and E2 (ubiquitin-conjugating enzyme), which prepare small protein tags called ubiquitin.
The third enzyme in this cascade is the E3 ubiquitin ligase. Over 600 different E3 ligases exist in humans, each designed to recognize specific target proteins. An E3 ligase recruits the E2 enzyme, loaded with ubiquitin, and transfers ubiquitin tags onto the target protein. This tagging process, often involving the attachment of multiple ubiquitin molecules in a chain, marks the protein for destruction.
Molecular glue degraders intervene in this natural pathway by acting as a bridge between an E3 ubiquitin ligase and a target protein the ligase would not normally recognize. The glue binds to one of the proteins, often the E3 ligase, reshaping its surface. This modification creates a new binding interface complementary to a surface on the target protein.
The formation of this three-part assembly, consisting of the E3 ligase, the molecular glue, and the target protein, is known as a “ternary complex.” Once this complex is stabilized, the E3 ligase can then attach ubiquitin tags to the now-recruited target protein. These ubiquitin tags act as a signal, directing the tagged protein to the proteasome, a large protein complex.
Inside the proteasome, the ubiquitinated target protein is unfolded and broken down into smaller peptides and amino acids. These building blocks are reused by the cell to synthesize new proteins, and ubiquitin tags are recycled. This catalytic process allows a single molecular glue molecule to degrade many copies of the target protein.
Where Molecular Glues Come From
The discovery of molecular glue degraders involved serendipitous observations and rational design efforts. Some earliest examples were identified for other therapeutic purposes before their “molecular glue” mechanism was understood. For instance, naturally occurring compounds like thalidomide and its derivatives, lenalidomide and pomalidomide, were found to promote the degradation of specific proteins.
These immunomodulatory drugs (IMiDs) were later found to bind to the E3 ubiquitin ligase cereblon (CRBN), inducing it to interact with and ubiquitinate target proteins like IKZF1 and IKZF3. Plant hormones, such as auxin and jasmonate-isoleucine, also function as natural molecular glue degraders. Auxin, for example, mediates the degradation of AUX/IAA transcriptional repressors by promoting their interaction with the E3 ligase TIR1, influencing plant growth and development.
The identification of synthetic molecular glues involves high-throughput screening of chemical libraries to find compounds that induce desired protein-protein interactions. Researchers also employ structure-based drug design, using detailed structural information of E3 ligases and target proteins. This approach aims to rationally design small molecules that can bridge these two proteins, forming a stable ternary complex and degrading the target.
Transforming Medicine with Molecular Glues
Molecular glue degraders represent an advancement in medicine due to their advantages over conventional small-molecule inhibitors. A key benefit is their ability to target proteins previously considered “undruggable.” Many disease-causing proteins lack a well-defined binding pocket for traditional inhibitors, but molecular glues can induce new interactions on protein surfaces, allowing them to be targeted.
Molecular glues operate through a catalytic mechanism, meaning a small amount of the drug can degrade many copies of the target protein. This contrasts with inhibitors, which require high concentrations to continuously block protein activity. The sustained removal of the target protein can lead to more durable therapeutic effects and potentially overcome drug resistance.
This class of drugs shows promise across various disease areas, particularly in cancer and neurodegenerative disorders. In cancer, molecular glues can induce the degradation of oncogenic proteins that drive tumor growth. For neurodegenerative diseases, they offer a pathway to clear misfolded or aggregated proteins that contribute to neuronal damage. Molecular glues enable the degradation of problematic proteins, offering new treatment possibilities for previously untreatable conditions.