Imagine a therapy that forces rogue cancer-causing proteins to self-destruct. Molecular glues offer just that — a ground-breaking avenue in targeted protein degradation, especially when conventional cancer drugs fail. By Neelabh Datta.
These small molecules foster binding interactions between harmful proteins and degradation signallers known as E3 ubiquitin ligases - these effectively label cancer-causing proteins for destruction. It’s like setting up a molecular hit squad, where the ligase tags the unwanted protein with ubiquitin, a marker for its journey to the proteasome, the cellular waste-disposal unit. There, the protein is gobbled up and dismantled, no longer able to fuel disease progression. This approach is part of an emerging field in cancer pharmacology, where targeted protein degradation has taken the centre position.
A Process of Elimination
Unlike traditional therapies, which simply inhibit protein function, these strategies aim to eliminate the problematic proteins altogether. Two main techniques have emerged: PROTACs and molecular glues. PROTACs (Proteolysis-targeting chimaeras) use bifunctional molecules to bridge the gap between a target protein and an E3 ligase, promoting the degradation of the target (Nishiguchi et al., 2024). Molecular glues, however, bind monovalently to either the ligase or the target, encouraging them to form a complex with one another.
A recent breakthrough introduced a new variant of molecular glues: intramolecular bivalent glues (IBGs). They work not by linking separate proteins, but by manipulating different domains within the same target protein, creating a 'cis' interaction (Hsia et al., 2024). This forces the protein to fold in a way that makes it more attractive to E3 ligases. For example, researchers investigating BRD4, a protein involved in cancer progression, discovered that IBGs could link two domains within BRD4 itself, bringing it closer to E3 ligases. This tightens the target-ligase relationship and leads to BRD4 degradation (Hsia et al., 2024).
Figure 1: Three-dimensional protein models displaying how intramolecularly bivalent and monovalent glues’ and PROTAC’s interactions with their targets vary. Red and orange indicate BRD4’s two bromodomains BD2 and BD1 respectively; yellow corresponds to the E3 ligase DCAF16 mentioned below; blue corresponds to DDB1, a protein which connects DCAF16 to a larger functional complex [Reproduced image of Fig. 5 h from source: Hsia, O., Hinterndorfer, M., Cowan, A.D. et al. Targeted protein degradation via intramolecular bivalent glues. Nature 627, 204–211 (2024). https://doi.org/10.1038/s41586-024-07089-6].
Why Molecular Glues Will Stick
The potential applications of molecular glues are staggering. While initial studies have focused on cancerous proteins like BRD4, which is linked to BET bromodomain inhibition, researchers believe that this strategy could work for a much wider target range (Hsia et al., 2024). BET proteins, often considered the gatekeepers of gene expression, manage the activity of genes associated with cell growth and survival. However, like an overzealous manager who can't stop delegating tasks, when these proteins become overactive, they can turn an otherwise well-regulated process into a cancerous frenzy, driving unchecked cell proliferation.
Enter BET inhibitors which degrade these proteins, cutting off growth signals and slowing tumour development. After all, most human proteins feature multiple domains, making them susceptible to the intramolecular glue approach. Even with suboptimal ligand binding, molecular glues like IBG1 and IBG4 can degrade targets at nanomolar concentrations, proving that molecular glues could potentially tackle many undruggable proteins (Hsia et al., 2024).
Despite their promise, molecular glues also present certain challenges. Unlike PROTACs, which can use a variety of ligase-target combinations, molecular glues rely heavily on pre-existing but weak interactions between the target and the E3 ligase. In the case of IBG1 and IBG4, the E3 ligases (DCAF16 and DCAF11, respectively) already had a faint affinity for BRD4 (Hsia et al., 2024). This supports the idea that molecular glues simply amplify pre-existing protein interactions, enhancing their stability to promote targeted degradation without initiating new binding events. It also suggests that while molecular glues are a powerful tool, their effectiveness may depend on how well these naturally occurring affinities can be exploited.
Lenalidomide: A Step in the Right Direction
Lenalidomide, an immunomodulatory imide drug, is a shining example of how molecular glues are being effectively used to combat cancer. It targets and degrades transcription factors critical for multiple myeloma progression, a significant feat that rewires the cancer cells' inner workings, removing their ability to survive. This drug also targets casein kinase 1A1 (CK1α), a key protein in myelodysplastic syndrome (MDS), especially in patients with a deletion of chromosome 5q (Nishiguchi et al., 2024). Its effectiveness is enhanced by CK1α haploinsufficiency — where the loss of one gene copy reduces protein levels, increasing cancer cell vulnerability. However, in cancers like acute myeloid leukaemia (AML), Lenalidomide's effectiveness diminishes, likely due to the cancer cells’ complex genetic architecture, making CK1α degradation less efficient. Despite this, the future remains bright with potent CK1α degraders like SJ3149 being developed, offering hope that molecular glues can soon extend their cancer-fighting abilities beyond MDS to AML to other malignancies (Nishiguchi et al., 2024).
Despite the field of molecular glues being still in its infancy, it has the potential to revolutionise cancer treatment. From BET bromodomain proteins to CK1α, these molecules are already showing impressive efficacy in various cancer models and can degrade almost any pathological protein! As more E3 ligases are explored, could molecular glues ultimately become a universal tool in our fight against cancer and beyond?
References
Cover Image: https://www.freeimages.com/photo/foam-1323737
Hsia, O., Hinterndorfer, M., Cowan, A.D. et al. Targeted protein degradation via intramolecular bivalent glues. Nature 627, 204–211 (2024). https://doi.org/10.1038/s41586-024-07089-6
Nishiguchi, G., Mascibroda, L.G., Young, S.M. et al. Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines. Nat Commun 15, 482 (2024). https://doi.org/10.1038/s41467-024-44698-1
