SPR-measured dissociation kinetics of PROTAC ternary complexes influence target degradation rate
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Abstract
ABSTRACT Bifunctional degrader molecules, known as proteolysis-targeting chimeras (PROTACs), function by recruiting a target to an E3 ligase, forming a target:PROTAC:ligase ternary complex. Despite the importance of this key intermediate species, no detailed validation of a method to directly determine binding parameters for ternary complex kinetics has been reported, and it remains to be addressed whether tuning the kinetics of PROTAC ternary complexes may be an effective strategy to improve the efficiency of targeted protein degradation. Here, we develop an SPR-based assay to quantify the stability of PROTAC-induced ternary complexes by measuring for the first time the kinetics of their formation and dissociation in vitro using purified proteins. We benchmark our assay using four PROTACs that target the bromodomains (BDs) of BET proteins Brd2, Brd3 and Brd4 to the E3 ligase VHL. We reveal marked differences in ternary complex off-rates for different PROTACs that exhibit either positive or negative cooperativity for ternary complex formation relative to binary binding. The positively cooperative degrader MZ1 forms comparatively stable and long-lived ternary complexes with either Brd4 BD2 or Brd2 BD2 and VHL. Equivalent complexes with Brd3 BD2 are destabilised due to a single amino acid difference (Glu/Gly swap) present in the bromodomain. We observe that this difference in ternary complex dissociative half-life correlates to a greater initial rate of intracellular degradation of Brd2 and Brd4 relative to Brd3. These findings establish a novel assay to measure the kinetics of PROTAC ternary complexes and elucidate the important kinetic parameters that drive effective target degradation.
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Multiple studies have reported that the stability of the E3-degrader-POI ternary complex may influence degradation kinetics and selectivity, and may be a more reliable predictor for degradation than target engagement alone.
“Multiple studies have reported that the stability of the E3-degrader-POI ternary complex may influence degradation kinetics and selectivity, and may be a more reliable predictor for degradation than target engagement alone (Bondeson et al., 2018; Roy et al., 2019).”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Roy et al., 2019
An essential step in targeted protein degradation is the drug-induced formation of a ternary complex.
“An essential step in targeted protein degradation is the drug-induced formation of a ternary complex10,43.”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [43]
Many effective PROTACs exhibit cooperativity in assembling the components of the ternary complex, implying the presence of adventitious favorable interactions between the target protein and the E3 ligase in the ternary complex.
“The observation that many effective PROTACs exhibit cooperativity in assembling the components of the ternary complex 35, 52, 53 implies the presence of adventitious favorable interactions between the target protein and the E3 ligase in the ternary complex.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [53]
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- Authors
- Roy, M. J., Winkler, S., Hughes, S. J., Whitworth, C., Galant, M., Farnaby, W., Rumpel, K., & Ciulli, A.
- Affiliations
- University of Dundee (GB)
- Boehringer Ingelheim (Germany) (DE)
- Corresponding author
- Ciulli, Alessio
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-02-05
- Volume
- 14
- Issue
- 3
- Pages
- 361-368
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- PMC
- PMC6423499
- OpenAlex
- W2914587883
- Cited by
- 386
- References
- 30
- Citations by year
- 2026: 63 · 2025: 67 · 2024: 58 · 2023: 50 · 2022: 48 · 2021: 41 · 2020: 38 · 2019: 20
- FWCI
- 12.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- ACS Chemical Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (094090/Z/10/Z, 100476/Z/12/Z)
- FP7 Ideas: European Research Council (311460)
- Boehringer Ingelheim
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- PROTACs, surface plasmon resonance, targeted protein degradation, E3 ubiquitin ligase, VHL, bromodomain, BRD4, BRD2, BRD3, MZ1, cooperativity, protein-protein binding, degradation rate
- MeSH terms
- Amino Acids, Kinetics, Protein Binding, Protein Conformation, Transcription Factors, Drug Design, Surface Plasmon Resonance, Ubiquitin-Protein Ligases, Proteolysis
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