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June 12, 2025

How Depixus’ MAGNA One™ can accelerate the development of novel molecular glues

Molecular glues are a promising new class of therapeutics for many diseases, but discovering and characterizing them is a challenge. By enabling researchers to measure thousands of individual protein interactions in real time, Depixus MAGNA One™ is set to revolutionize the development of these exciting novel drugs.

Molecular glues – small molecules that facilitate protein-protein interactions (PPIs) – are an exciting new therapeutic approach for cancer and other conditions such as inflammatory and neurodegenerative disorders.1,2

However, discovering and developing novel molecular glues is far from simple. PPIs can be weak or transient, and the ternary complexes formed by the action of molecular glues can be challenging to study using traditional analytical methods.

As a result, molecular glues cannot be rationally designed in the same way as many other drug classes and are usually discovered through screening or serendipity.

Breaking through this bottleneck, Depixus’ MAGNA One™ is an award-winning, user-friendly magnetic force spectroscopy (MFS) instrument that can analyze thousands of individual PPIs in parallel, accelerating the development of novel molecular glues for a wide range of diseases.

What Are Molecular Glues?

Molecular glues are small molecules that facilitate an interaction between proteins that wouldn’t normally interact or stabilize an interaction that already exists.

They grew out of work on PROTACs (proteolysis-targeting chimeras) – larger bifunctional molecules that induce an interaction between the target protein and an E3 ligase, marking the target for subsequent degradation by the proteasome.3

There has been some clinical success for this approach, most notably Arvinas and Pfizer’s Vepdegestrant (ARV-471) which targets the estrogen receptor (ER) and is currently in phase III for ER+ breast cancer.4

Compared with PROTACs, molecular glues are typically smaller, single-molecule entities, often with improved physicochemical properties, and therefore expected to be better drugs.

The most common form of molecular glues, known as molecular glue degraders, also target a protein for proteasomal destruction by the E3 ubiquitination pathway. They either bind to the E3 ligase and alter its surface to promote binding with the target protein, or bind to the target protein and induce binding to the E3 ligase.5

Examples of molecular glues

Examples of existing molecular glues include the immunomodulatory imide drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide, also known as Cereblon E3 ligase modulators. They were initially approved by the FDA for treating myeloma based on their efficacy and subsequently discovered to be molecular glues.6

IMiDs induce a conformational change in the protein Cereblon, part of the Cullin Ring Ligand 4 E3 ubiquitin ligase complex (CRL4CRBN), which enables it to recruit transcription factors including IKZF1 (Ikaros) and IKZF3 (Aiolos). This interaction, which would not normally happen inside cells, leads to transcription factor ubiquitination and degradation with downstream impacts on cancer cell growth and viability.7

In addition to IKZF1 and IKZF3, other molecular glue targets under investigation include Cyclin K, Casein Kinase 1α, RNA Binding Motif Protein 39 (RBM39), and GSPT1 for a range of oncology indications.8,9

For example, molecular glues targeting GSPT1 degradation via CRBN modulation include Celgene’s CC-885 and its rationally designed derivative CC-9000910, which has now completed phase I trials for relapsed/refractory acute myeloid leukemia (#NCT02848001 and #NCT04336982).

Challenges in discovering and developing molecular glues

Unlike PROTACs, which have a predictable mechanism of action and can be rationally designed, it is challenging to identify, characterize, and optimize molecular glues using conventional analytical tools.

Instead, researchers must rely on serendipity (as in the case of the IMiDs) or activity-based screening. Proximity-based assays such as time-resolved fluorescence energy transfer (TR-FRET), amplified luminescent proximity homogeneous assays (AlphaScreen / AlphaLISA), and fluorescence polarization are being increasingly used in the hope of streamlining the search.11,12

Based on knowledge from PROTACs, formation of a highly stable ternary complex between the target proteins and the molecular glue is crucial for effective ubiquitination and degradation.13 However, no single technique meets all the requirements for characterizing these complexes in sufficient detail to inform drug development.

Measuring physical and thermodynamic parameters such as binding affinities and kinetics can be achieved with a combination of techniques such as Isothermal Titration Calorimetry (ITC), Surface Plasmon Resonance (SPR), Bio-layer Interferometry (BLI), or Microscale Thermophoresis (MST).14 These methods only produce bulk average data and fail to capture potentially vital information about sub-populations and rare or weak binding events, limiting their utility.

By contrast, higher-resolution techniques such as X-ray crystallography, cryo-electron microscopy, or nuclear magnetic resonance (NMR) spectroscopy can provide insights into what’s happening within individual protein complexes. But these methods only capture static molecules, and miss dynamic, weak or transient interactions.

Using Depixus MAGNA One to study molecular glues

Based on magnetic force spectroscopy (MFS), Depixus MAGNA One™ is an award-winning user-friendly biophysical instrument system that allows real-time, label-free, non-destructive analysis of thousands of individual biomolecular interactions in parallel.

By delivering single molecule insights at scale, Depixus MAGNA One can detect rare, weak and heterogeneous interactions that would be missed by bulk average analysis. This makes it ideally suited to studying protein-protein interactions, including the ternary complexes formed by molecular glues and their targets.

It works by tethering pairs of proteins, such as the target and E3 ligase, to a nucleotide scaffold. Many thousands of these scaffolds are attached to the surface of a flow cell in a precise grid array, with a tiny paramagnetic bead attached to the free end. The movement of the scaffold, and therefore the interactions between the proteins, is measured by tracking the vertical position of each bead with nanometer-range precision.

When the two proteins are not interacting, the scaffold and attached bead move freely due to Brownian motion. Upon addition of a molecular glue, the proteins are ‘stuck’ together and the movement of the bead is restricted. This can be tracked in real-time, allowing relevant kinetic parameters to be calculated.

As an example, Depixus MAGNA One™ was used to visualize the ternary complexes formed by the CRBN/DDB1 proteins of the CRL4CRBN E3 ligase and the transcription factor IKZF1 upon addition of the molecular glue degrader lenalidomide. After addition of lenalidomide (100 nM) the formation of a stable ternary complex could be visualized by a sharp reduction in the motion of the bead (Figure 1).

 

Figure 1: Two example real-time Depixus MAGNA One™ data streams showing the E3 ubiquitin complex CRBN/DDB1 and the neo-target IKZF1 (a transcription factor), which do not normally interact (left graph). Following addition of 100 nM lenalidomide (right graph), the two proteins form a stable ternary complex, indicated by the red bar.

Accelerating the development of molecular glues with Depixus MAGNA One

The precise biomolecular insights delivered by Depixus MAGNA One make it a valuable new technology to accelerate the discovery and development of molecular glues. This approach is equally applicable to the development of PROTACs or any other modulator of protein-protein interactions, whether an inducer, stabilizer or inhibitor.

Going beyond degraders, there are other exciting therapeutic modalities in the pipeline based on inducing or stabilizing PPIs, such as small molecules designed to modulate signal transduction, chromatin remodeling, protein transport, transcription and more.15

By harnessing the power of scalable magnetic force spectroscopy in a user-friendly laboratory instrument, Depixus MAGNA One opens a new chapter in our understanding of how proteins interact and generates an unprecedented richness of data to support molecular biology and drug development research.

Download our app note to learn more about using Depixus MAGNA One to study molecular glues.

Book a call with one of our team to discover how Depixus MAGNA One can accelerate your molecular glue research.

References:

  1. Soini L, et al. Molecular glues to stabilise protein-protein interactions. Curr Opin Chem Biol. 2022 69:102169. Doi: 10.1016/j.Cbpa.2022.102169.
  2. Schreiber SL. The Rise of Molecular Glues. Cell. 2021 Jan 7;184(1):3-9. doi: 10.1016/j.cell.2020.12.020.
  3. Sakamoto KM, et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8554-9. doi: 10.1073/pnas.141230798.
  4. E. P. Hamilton et al. “VERITAC-2: a Phase III study of Vepdegestrant, a PROTAC ER degrader, versus fulvestrant in ER+/HER2- advanced breast cancer.“ Future Oncol. 2024;20(32):2447-2455. doi: 10.1080/14796694.2024.2377530.
  5. Sasso JM, et al. Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic. Biochemistry. 2023 Feb 7;62(3):601-623. doi: 10.1021/acs.biochem.2c00245.
  6. Asatsuma-Okumura T, Ito T, Handa H. Molecular mechanisms of cereblon-based drugs. Pharmacol Ther. 2019 Oct;202:132-139. doi: 10.1016/j.pharmthera.2019.06.004.
  7. Lu G, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science. 2014 Jan 17;343(6168):305-9. doi: 10.1126/science.1244917.
  8. Zou T, Lin Z. The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression. Int J Mol Sci. 2021 May 27;22(11):5754. doi: 10.3390/ijms22115754.
  9. Matyskiela ME, et al. A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase. Nature. 2016 Jul 14;535(7611):252-7. doi: 10.1038/nature18611.
  10. Surka C, et al. CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells. Blood. 2021 Feb 4;137(5):661-677. doi: 10.1182/blood.2020008676.
  11. Holdgate GA, et al. Screening for molecular glues – Challenges and opportunities. SLAS Discov. 2024 Mar;29(2):100136. doi: 10.1016/j. slasd.2023.12.008.
  12. Dewey JA, et al. Molecular Glue Discovery: Current and Future Approaches. J Med Chem. 2023 Jul 27;66(14):9278-9296. doi: 10.1021/acs.jmedchem.3c00449.
  13. Wurz RP, et al. Affinity and cooperativity modulate ternary complex formation to drive targeted protein degradation. Nat Commun. 2023 Jul 13;14(1):4177. doi: 10.1038/s41467-023-39904-5.
  14. Ward JA, Perez-Lopez C, Mayor-Ruiz C. Biophysical and Computational Approaches to Study Ternary Complexes: A ‘Cooperative Relationship’ to Rationalize Targeted Protein Degradation. Chembiochem. 2023 May 16;24(10):e202300163. doi: 10.1002/cbic.202300163.
  15. Stanton BZ, Chory EJ, Crabtree GR. Chemically induced proximity in biology and medicine. Science. 2018 Mar 9;359(6380):eaao5902. doi: 10.1126/science.aao5902.