Proteins are the material basis of life and are the main bearers of life activities. The structure of proteins determines their functions. Changes in the conformation and quantity of proteins often lead to the occurrence of diseases. The fundamental approach to treating many diseases is to selectively regulate protein function using small molecules. However, traditionally, only a small number of proteins can be regulated through this mechanism. Approximately 80% of disease-related protein targets lack defined pockets for ligand interaction, making rational drug design a huge challenge. These are commonly referred to as "non-druggable" target proteins.

Scientists designed and utilized the two natural protein degradation systems such as ubiquitin–proteasome system (UPS) and lysosomal system, to degrade proteins associated with diseases, thereby achieving therapeutic effects for the treatment of diseases.

Among them, technologies associated with lysosomes mainly include Lysosome Targeting Chimeras (LYTACs), Autophagy-Targeting Chimeras (AUTACs), and Autophagosome-Tethering Compounds (ATTECs), which are primarily applicable to cell membrane proteins and organelles.

The targeted protein degradation technologies based on the UPS mainly include Proteolysis-Targeting Chimeras (PROTACs) and molecular glues. Here, the article mainly introduces the molecular glue technology.

Molecular Glues

Molecular glues are small molecules that induce proximity between a target protein and an effector macromolecule, which facilitates the dimerization or colocalization of two proteins via forming a ternary complex. They can regulate a variety of biological processes, such as transcription, chromatin regulation, protein folding, localization, and degradation.

Figure 1.  Molecular glue [1]

In 1991, the concept of molecular glue was first proposed, with cyclosporin A and FK506 acting as molecular glues. In 1996, the first designed and synthesized molecular glue, FK1012, was used in mouse studies. Around the year 2000, Rapamycin was approved by the FDA as immunosuppressant, and subsequently, Rapamycin analogs were introduced to the market. After 2014, molecular glue degraders emerged, and currently, some of them have entered clinical research.

Molecular Glues VS. PROTACs

PROTAC and molecular glue are two main modes of targeted protein degradation technology based on the UPS (Figure 2). In the case of PROTAC, it recruits E3 ubiquitin ligase, inducing the proximity of the target protein to E3 ubiquitin ligase, leading to ubiquitination and degradation of the target protein. On the other hand, molecular glue modifies the surface of the ubiquitin ligase, promoting or inducing protein-protein interactions (PPI) between E3 ubiquitin ligase and the target protein, resulting in ubiquitination and subsequent degradation of the target protein.

In addition, the target proteins and mechanisms of PROTACs can be predicted, allowing for rational design based on the binding mode of the ligand with the target protein. In contrast, the discovery of molecular glues is often serendipitous, lacking systematic discovery methods and rational design strategies. Molecular glues cannot be obtained through large-scale screening of components as easily as PROTACs. Consequently, the number of discovered molecular glue degraders is currently quite limited. The current discovery strategies for molecular glues mainly include: 1. High-throughput screening, 2. Discovery from natural products, and 3. Chemical genomics screening.

The advantage of molecular glue lies in its ability to degrade proteins without ligand binding by promoting protein-protein interactions (PPI) between ubiquitin ligase and the target protein, demonstrating superior therapeutic effects compared to small molecule drugs. However, PROTACs often have high molecular weight (MW), poor cell permeability and pharmacokinetic (PK) characteristics, which hinder their development in clinical treatment. Molecular glue, on the other hand, has a lower molecular weight, higher cell permeability, and better oral absorption, showing better drugable properties. Therefore, molecular glues exhibit significant clinical potential.

Figure 2. Schematic presentation of (A) a molecular glue or (B) a PROTAC [3]

Latest Research Progress on Molecular Glues

Currently, there are three molecular glues approved for marketing worldwide, including lenalidomide and its derivatives (pomalidomide and thalidomide). These three drugs have been approved by the U.S. FDA for their immunomodulatory, anti-inflammatory, and anti-tumor effects, and are used in the treatment of diseases such as multiple myeloma.

The molecular weights of these three molecular glue compounds are all below 300 Da. They function by recruiting the E3 ubiquitin ligase CRBN to degrade target proteins, including the transcription factors IKZF1/3. Additionally, analogs of lenalidomide, such as (R)-lenalidomide, are commonly used as E3 ubiquitin ligase ligands in many PROTAC molecules.

Figure 3. Approved molecular glues

Furthermore, many molecular glue compounds are currently in clinical research. Several pharmaceutical companies, including Novartis, Bayer, BMS, and other pharmaceutical giants, are actively involved in the development of molecular glue compounds.

Table 1. Molecular glues in clinical trials

Conclusion

Although the development of molecular glue drugs is still in its early stages, and the discovery of such drugs involves a significant element of serendipity, with continuous breakthroughs and innovations in drug development technologies, we believe that more molecular glue drugs will be approved for clinical use.

References:
[1] Dong G, Ding Y, He S, Sheng C. Molecular Glues for Targeted Protein Degradation: From Serendipity to Rational Discovery. J Med Chem. 2021;64(15):10606-10620. doi:10.1021/acs.jmedchem.1c00895
[2] Zhao, L., Zhao, J., Zhong, K. et al. Targeted protein degradation: mechanisms, strategies and application. Sig Transduct Target Ther 7, 113 (2022). https://doi.org/10.1038/s41392-022-00966-4
[3] Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic, Janet M. Sasso, Rumiana Tenchov, DaSheng Wang, Linda S. Johnson, Xinmei Wang, and Qiongqiong Angela Zhou, Biochemistry 2023 62 (3), 601-623, DOI: 10.1021/acs.biochem.2c00245