The Development And Research Status of Molecular Glue

At present, there are two main types of protein degraders. One is PROTAC, which degrades target proteins through ubiquitin-proteasome pathway. The other type is molecular glue, which also binds ubiquitinated ligases. But unlike PROTACs, molecular glues induce protein degradation by inducing PPI between ubiquitin ligases and substrates, which can degrade non-druggable target proteins , does not require a binding pocket on the target protein.

Molecular glue refers to a class of small molecular compounds that can mediate protein-protein interaction. It can promote dimerization or co-localization of two proteins by forming ternary complexes, thus producing a variety of biological and pharmacological functions.

The Development History of Molecular Glue

The concept of molecular glue was first proposed in the early 1990s. The immunosuppressants cyclosporin A (CsA) and FK506 are the first molecular glues. Although CsA and FK506 have different direct receptors, which are cyclosporine and FKBP respectively, the mechanism of inducing cell signal transduction is similar, both of which depend on the action of calcineurin (CaN). Subsequently, the immunosuppressive agent Rapamycin (Rapamycin) was approved by FDA, and rapamycin analogues successively came to market. With the development of structural biology, the mechanism of these molecular gelles has been clarified. FK506 induces dimerization between FK506 and calcineurin mainly through protein interaction (PPIs), while rapamycin stabilizes terpolymer complex through direct interaction with two proteins. This new mechanism of chemically induced protein recombination is emerging as an effective strategy for exploring biological processes and developing therapeutic agents, and it has inspired the discovery of molecular gels from natural products and synthetic molecules. In recent years, molecular glue depressants have gradually emerged, and molecular glue degraders have entered clinical studies.

Although both molecular glues and PROTACs are bifunctional protein degraders, they have different mechanisms of action and structural features:

① Molecular glue is a small molecule degraders, which mainly induces PPI between E3 ligase and target protein to form a ternary complex, resulting in protein ubiquitination and degradation by proteasome. While PROTACs induce target proteins to approach E3 ligases, leading to target ubiquitination and degradation, in some cases, PROTACs can also induce PPIs between target proteins and E3 ligases.

② Most PROTACs are rationally designed according to the binding mode of the ligand and the target protein, and then select the appropriate site in the ligand to expand the linker and E3 ligase binding group. Therefore, the target proteins and molecular mechanisms of PROTACs can be predicted. However, so far, the discovery of molecular glue degraders has been largely serendipitous, and molecular glues can mediate interactions with a wide range of targets, are difficult to predict accurately, and exhibit diverse biological activities.

③ Generally speaking, the molecular weight of molecular glue is very small, which is convenient for optimizing the physical and chemical properties. However, PROTACs generally have a large molecular weight and do not meet the five principles of drug-like, so their bioavailability is low and their pharmacokinetic properties are poor.

Research Status of Molecular Glue

Due to the better pharmaceutical-like properties of molecular glues, there are currently some inhibitors in clinical research, but the research on molecular adhesives is still in its infancy, and most of the molecular glue degraders were discovered accidentally. There is still a long way to go before molecular adhesives can be reasonably developed into therapeutic agents.

Conclusion

Targeting protein degradation is emerging as a promising approach in drug discovery and development. Molecular glue avoids the limitations of traditional inhibitors, making some targets change from "undruggable" to "druggable". Although considerable resources have been devoted to designing PROTACs, molecular glues have inherent advantages as drug-like small molecule protein degraders. For example lower molecular weight, higher cell permeability and better oral absorption. Molecular glues thus offer an alternative approach for innovative drug discovery targeting protein degradation. Although the molecular glue degrading agent is very ideal, there are still very few molecular glue degrading agents discovered so far. The discovery process is very accidental, and there is a lack of a systematic discovery and design strategy. Therefore, the rational development of molecular glue inhibitors still needs to be further developed. exploration.

PROTAC and molecular glues are the two main modes of targeted protein degradation technology based on the ubiquitin-proteasome system. Biopharma PEG is a professional PEG supplier provides multi-functionalized PEG derivatives as PROTAC linkers to customers all over the world .

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