Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity
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Abstract
Bivalent proteolysis-targeting chimeras (PROTACs) drive protein degradation by simultaneously binding a target protein and an E3 ligase and forming a productive ternary complex. We hypothesized that increasing binding valency within a PROTAC could enhance degradation. Here, we designed trivalent PROTACs consisting of a bivalent bromo and extra terminal (BET) inhibitor and an E3 ligand tethered via a branched linker. We identified von Hippel-Lindau (VHL)-based SIM1 as a low picomolar BET degrader with preference for bromodomain containing 2 (BRD2). Compared to bivalent PROTACs, SIM1 showed more sustained and higher degradation efficacy, which led to more potent anticancer activity. Mechanistically, SIM1 simultaneously engages with high avidity both BET bromodomains in a cis intramolecular fashion and forms a 1:1:1 ternary complex with VHL, exhibiting positive cooperativity and high cellular stability with prolonged residence time. Collectively, our data along with favorable in vivo pharmacokinetics demonstrate that augmenting the binding valency of proximity-induced modalities can be an enabling strategy for advancing functional outcomes.
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The degradation efficacy of PROTACs is influenced by valence number, and the trivalent PROTAC SIM1 exhibits significantly enhanced degradation compared to its divalent counterpart.
“Researchers discovered that the degradation efficacy of PROTACs is influenced by valence number. The trivalent PROTAC named SIM1, developed by Satomi Imaide’s team, exhibited significantly enhanced degradation compared to its divalent counterpart.521”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [521]
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Aptamer-Based Targeted Protein Degradation
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Target protein localization and its impact on PROTAC-mediated degradation
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Strategies for the discovery of oral PROTAC degraders aimed at cancer therapy
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Sulfatase-Induced In Situ Formulation of Antineoplastic Supra-PROTACs
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Targeted Biomolecule Regulation Platform: A Split-and-Mix PROTAC Approach
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A comprehensive review of BET-targeting PROTACs for cancer therapy
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Key Considerations in Targeted Protein Degradation Drug Discovery and Development
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The efflux pump ABCC1/MRP1 constitutively restricts PROTAC sensitivity in cancer cells
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Intrinsic signaling pathways modulate targeted protein degradation
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TACkling Cancer by Targeting Selective Protein Degradation
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Novel Amphiphilic PROTAC with Enhanced Pharmacokinetic Properties for ALK Protein Degradation
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High‐Throughput Miniaturized Synthesis of PROTAC‐Like Molecules
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- Authors
- Imaide, S., Riching, K. M., Makukhin, N., Vetma, V., Whitworth, C., Hughes, S. J., Trainor, N., Mahan, S. D., Murphy, N., Cowan, A. D., Chan, K.-H., Craigon, C., Testa, A., Maniaci, C., Urh, M., Daniels, D. L., & Ciulli, A.
- Affiliations
- University of Dundee (GB)
- Promega (United States) (US)
- Corresponding author
- Daniels, Danette L.
- Ciulli, Alessio
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2021-10-21
- Volume
- 17
- Issue
- 11
- Pages
- 1157-1167
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC7611906
- OpenAlex
- W3205001044
- Semantic Scholar
- 8e332350826646e57b57de209660d026df6f461d
- Cited by
- 251
- References
- 62
- Citations by year
- 2026: 38 · 2025: 59 · 2024: 57 · 2023: 45 · 2022: 44 · 2021: 8
- FWCI
- 12.33
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Chemical Biology (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- ChemRxiv (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Wellcome Trust (094090/Z/10/Z, strategic awards to Dundee 100476/Z/12/Z and 094090/Z/10/Z, 100476/Z/12/Z)
- Ono Pharmaceutical
- European Research Council (Starting Grant ERC-2012-StG-311460 DrugE3CRLs)
- 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
- protein degradation, BET inhibitors, SIM1, BRD2, avidity, positive cooperativity, ternary complex, anticancer activity, pharmacokinetics
- MeSH terms
- Humans, Ubiquitin-Protein Ligases, Proteolysis
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