Targeted protein degradation via intramolecular bivalent glues
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Abstract
Targeted protein degradation is a pharmacological modality that is based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal degradation. This has been achieved either via proteolysis-targeting chimeras (PROTACs)—bifunctional compounds composed of two separate moieties that individually bind the target and E3 ligase, or via molecular glues that monovalently bind either the ligase or the target 1–4 . Here, using orthogonal genetic screening, biophysical characterization and structural reconstitution, we investigate the mechanism of action of bifunctional degraders of BRD2 and BRD4, termed intramolecular bivalent glues (IBGs), and find that instead of connecting target and ligase in trans as PROTACs do, they simultaneously engage and connect two adjacent domains of the target protein in cis . This conformational change ‘glues’ BRD4 to the E3 ligases DCAF11 or DCAF16, leveraging intrinsic target–ligase affinities that do not translate to BRD4 degradation in the absence of compound. Structural insights into the ternary BRD4–IBG1–DCAF16 complex guided the rational design of improved degraders of low picomolar potency. We thus introduce a new modality in targeted protein degradation, which works by bridging protein domains in cis to enhance surface complementarity with E3 ligases for productive ubiquitination and degradation.
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TR-FRET and fluorescence polarization assays offer robust scalable formats for detecting molecular glue-induced interactions in vitro.
“Similarly, tR-FRet and fluorescence polarization (FP) assays offer robust scalable formats for detecting molecular glue-induced interactions in vitro (Simonetta et al. 2019;wang et al. 2021;Hsia et al. 2024;Kozicka et al. 2024).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Hsia et al. 2024
The Methods (TR-FRET proximity assay; page unavailable) describe plate-based assays for compound-induced BRD4–DCAF complex formation and stabilization. The Methods (Fluorescence polarization assay; page unavailable) describe a 384-well assay measuring binding of a fluorescent sulfonamide probe to individual proteins, not detection of glue-induced protein–protein interactions. The paper therefore supports the TR-FRET part and the use of plate-based formats, but not the claim that both assays detect those interactions or that their robustness was established. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNanoBiT, NanoBRET and HiBiT technologies enable sensitive detection of ternary complex formation and/or target degradation in live cells and cell extracts.
“techniques using NanoBit®, NanoBRet® and HiBit® technologies enable sensitive detection of ternary complex formation and/or target degradation, both in live cells and cell extracts, making them particularly well-suited for identifying glue-induced degradation events (Bell et al. 2024;Hsia et al. 2024;ismail et al. 2024).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Hsia et al. 2024
The Methods sections on HiBiT degradation assays and kinetic ubiquitination and degradation assays describe luminescence measurements of target degradation in cells and after cell lysis, alongside NanoBRET measurements. However, the paper uses a separate TR-FRET proximity assay to measure ternary-complex formation; it does not show that its NanoBRET or HiBiT assays detect ternary complexes, or explicitly characterize these methods as sensitive across both live cells and cell extracts. No page numbers are supplied in our copy. (LLM, conf=0.84)
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TET3-overexpressing macrophages promote endometriosis
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Discovery of Potent and Selective BCL6 Ligand-Directed Degrader (LDD), BCL6-760
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“Similarly, tR-FRet and fluorescence polarization (FP) assays offer robust scalable formats for detecting molecular glue-induced interactions in vitro (Simonetta et al. 2019; wang et al. 2021; Hsia et al. 2024; Kozicka et al. 2024).”
A patent review of BRD4 inhibitors (2020–present)
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Opportunities in proximity modulation: Bridging academia and industry
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Self-citationHistone lysine methylation modifiers controlled by protein stability
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- Authors
- Hsia, O., Hinterndorfer, M., Cowan, A. D., Iso, K., Ishida, T., Sundaramoorthy, R., Nakasone, M. A., Imrichova, H., Schätz, C., Rukavina, A., Husnjak, K., Wegner, M., Correa-Sáez, A., Craigon, C., Casement, R., Maniaci, C., Testa, A., Kaulich, M., Dikic, I., Winter, G. E., & Ciulli, A.
- Affiliations
- University of Dundee (GB)
- Austrian Academy of Sciences (AT)
- Goethe University Frankfurt (DE)
- Corresponding author
- Winter, Georg E.
- Ciulli, Alessio
- ORCID
- Hsia, Oliver
- Hinterndorfer, Matthias
- Cowan, Angus D.
- Iso, Kentaro
- Ishida, Tasuku
- Sundaramoorthy, Ramasubramanian
- Nakasone, Mark A.
- Imrichova, Hana
- Schätz, Caroline
- Rukavina, Andrea
- Husnjak, Koraljka
- Wegner, Martin
- Correa-Sáez, Alejandro
- Craigon, Conner
- Casement, Ryan
- Maniaci, Chiara
- Testa, Andrea
- Kaulich, Manuel
- Dikic, Ivan
- Winter, Georg E.
- Ciulli, Alessio
- Venue
- Nature
- Published
- 2024-02-21
- Volume
- 627
- Issue
- 8002
- Pages
- 204-211
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC10917667
- OpenAlex
- W4391994105
- Cited by
- 222
- References
- 78
- Citations by year
- 2026: 68 · 2025: 86 · 2024: 58 · 2023: 9
- FWCI
- 28.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, cc-by)
- Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by)
- Funders
- GlaxoSmithKline
- McGill University
- University of Dundee
- Wellcome Trust (223816/Z/21/Z)
- European Federation of Pharmaceutical Industries and Associations (FP7/20072013, 875510)
- Foghorn Therapeutics
- European Commission (223816, 2007–2013, FP7 2007-2013, HORIZON2020, H2020-MSCA-IF-2020, H2020, 101024945, FP7/2007, H2020‐MSCA‐IF, 875510, H2020-MSCA, 851478)
- European Synchrotron Radiation Facility (ID23-2)
- Österreichischen Akademie der Wissenschaften (IF-2020, P7909, P32125)
- Austrian Science Fund (P31690, P 32125, P7909)
- Universität Wien
- Eisai
- Medizinische Universität Wien
- Innovative Medicines Initiative (FP7/2007‐2013, 875510, H2020)
- Horizon 2020 Framework Programme (FP7/2007-2013, H2020-MSCA, H2020-MSCA-IF-2020, 875510)
- Medical Research Council
- H2020 Marie Skłodowska-Curie Actions (H2020-MSCA-IF-2020, H2020, H2020-MSCA-IF, MSCA-IF-2020, FP7/2007-2013, H2020-MSCA, HORIZON2020)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- targeted protein degradation, PROTACs, molecular glues, BRD4, BRD2, E3 ubiquitin ligase, ubiquitination, proteasomal degradation, ternary complex structure, bromodomain proteins
- MeSH terms
- Protein Domains, Bromodomain Containing Proteins, Proteolysis Targeting Chimera, Nuclear Proteins, Protein Binding, Substrate Specificity, Transcription Factors, Drug Design, Cell Cycle Proteins, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Ubiquitination, Proteolysis
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