Molecular glues represent a new category of small molecule drugs that work by bringing proteins together that do not typically interact. These compounds act as a bridge, promoting novel connections between specific proteins within the body. Their unique action opens new avenues for treating diseases that have been difficult to address with conventional medicines. This innovative approach holds significant promise for expanding therapeutic options.
The Unique Mechanism of Action
Molecular glues function by inducing proximity, where a small molecule facilitates interaction between two otherwise separate proteins. This forms a “ternary complex” of the glue and the two interacting proteins. The glue effectively acts like a piece of double-sided tape, binding to one protein and simultaneously presenting a surface that attracts and binds a second protein.
This induced proximity can lead to various outcomes, such as the activation of a new function, stabilization of existing protein interactions, or, frequently, the degradation of one of the proteins. For instance, some molecular glues bring a target protein close to an E3 ubiquitin ligase, part of the cell’s natural waste disposal system. This tags the target protein for destruction, removing the disease-causing protein from the cell.
Cooperative binding in the ternary complex contributes to molecular glue specificity. The molecular glue often first binds to a “presenter protein,” creating a modified protein with increased affinity for the target protein. This multi-step interaction allows for precise control over which proteins are brought together and its cellular effect.
Beyond Traditional Drug Approaches
Molecular glues offer a distinct advantage over traditional drugs, which often block or inhibit protein functions. Conventional medicines might, for example, occupy the active site of an enzyme to prevent it from carrying out its reactions or block a receptor to stop a signaling pathway. These methods primarily focus on deactivating unwanted protein activity.
In contrast, molecular glues actively create new interactions between proteins or induce their degradation. This represents a shift from “blocking” to “building” or “removing” protein functions within the cell. By recruiting a target protein to the cellular degradation machinery, molecular glues can eliminate disease-causing proteins rather than just inhibiting their activity.
This capacity to induce protein degradation or stabilize beneficial interactions provides a new strategy for drug discovery, especially for proteins previously considered “undruggable.” Many disease-causing proteins lack a suitable binding pocket for traditional inhibitors, but molecular glues can still engage them by leveraging the cell’s own protein machinery. Their ability to orchestrate the destruction of many copies of a pathogenic protein also provides high efficiency at lower doses.
Current and Future Therapeutic Uses
Molecular glues are being explored for treating a range of diseases, especially those driven by problematic protein function or accumulation. A focus area is cancer, where molecular glues can target specific oncoproteins for degradation. For example, thalidomide and its derivatives, lenalidomide and pomalidomide, were later understood to act as molecular glues, promoting the degradation of proteins like Ikaros and Aiolos, involved in blood cancers.
Beyond cancer, research is expanding into neurodegenerative diseases and inflammatory conditions. Their ability to induce protein degradation or modulate protein interactions makes them appealing for disorders where abnormal protein aggregation or dysregulation plays a role. While few proximity-inducing targeted protein degraders have reached advanced clinical testing, several are in development.
Potential applications extend to other areas where specific protein-protein interactions need regulation. Researchers are investigating how molecular glues could stabilize beneficial protein complexes or reprogram the binding partners of scaffolding proteins. This broad applicability stems from their unique ability to manipulate the protein landscape within cells, offering hope for new treatments in areas with unmet medical needs.
The Search for New Molecular Glues
Discovering new molecular glues often begins with high-throughput screening, testing vast libraries of small molecules for their ability to induce desired protein interactions or degradation. This approach can lead to serendipitous discoveries, as with thalidomide, whose molecular glue mechanism was understood retrospectively. Identifying these compounds relies on observing a specific cellular outcome, such as target protein degradation.
Once a potential molecular glue is identified, scientists use structural biology to understand how it binds to proteins and facilitates ternary complex formation. This structural information aids in the rational design of improved molecular glues, allowing researchers to modify compounds for better efficacy, specificity, and drug-like properties. Understanding the precise protein interfaces that the glue stabilizes is a complex but crucial part of this process.
The development of new molecular glues is an interdisciplinary effort, combining chemistry, structural biology, and cell biology. While some have been discovered by chance, there is a growing push towards more rational design strategies, especially for targeting “undruggable” proteins. This ongoing research aims to unlock the full therapeutic potential of this promising class of drugs.