Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4
Open accessAbstract
BRD4, a bromodomain and extraterminal domain (BET) family member, is an attractive target in multiple pathological settings, particularly cancer. While BRD4 inhibitors have shown some promise in MYC-driven malignancies such as Burkitt's lymphoma (BL), we show that BRD4 inhibitors lead to robust BRD4 protein accumulation, which may account for their limited suppression of MYC expression, modest antiproliferative activity, and lack of apoptotic induction. To address these limitations we designed ARV-825, a hetero-bifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BRD4 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation of BRD4 in all BL cell lines tested. Consequently, ARV-825 more effectively suppresses c-MYC levels and downstream signaling than small-molecule BRD4 inhibitors, resulting in more effective cell proliferation inhibition and apoptosis induction in BL. Our findings provide strong evidence that cereblon-based PROTACs provide a better and more efficient strategy in targeting BRD4 than traditional small-molecule inhibitors.
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PROTACs usually have a longer-lasting effect and require less systemic drug exposure to be effective than their corresponding payloads.
“These results are in agreement with the unique mechanism of action of PROTACs, that usually have a longer-lasting effect and require less systemic drug exposure to be effective than their corresponding “payloads”.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [39]
PROTACs act catalytically to induce protein degradation in a sub-stoichiometric manner and their effect is not limited by equilibrium occupancy.
“This is because PROTACs act catalytically to induce protein degradation in a sub-stoichiometric manner and their effect is not limited by equilibrium occupancy32,39.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [39]
PZ functioning as a PROTAC has a longer-acting activity than its corresponding inhibitor.
“We used a less intensive dosing schedule (i.e., 41 μmol/kg, once every 3 days or q3d) for this experiment because PZ functioning as a PROTAC has a longer-acting activity than its corresponding inhibitor39 (Fig. 3b).”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [39]
ARV825 is a hetero-bifunctional PROTAC that recruits BET family proteins to the E3 ubiquitin ligase CEREBLON, leading to fast, efficient, and prolonged degradation of BET family proteins.
“ARV825 is a hetero-bifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BET family proteins to the E3 ubiquitin ligase CEREBLON, leading to the fast, efficient, and prolonged degradation of BET family proteins24.”
From A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells (2020) · cites this paper as [24]
Long-term dosing or high concentrations associated with BET inhibitor treatment leads to obvious BRD4 protein accumulation and inefficient c-MYC suppression.
“In addition, long-term dosing or high concentrations associated with BETi treatment also leads to obvious BRD4 protein accumulation and inefficient c-MYC suppression [85].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [85]
PROTACs against BRD4, BTK, BCR-ABL and CDK-6 have shown efficacy in leukemia.
“For example, PROTACs against BRD4, BTK, BCR-ABL and CDK-6 etc. have shown efficacy in leukemia [22, 44, 58, 60], whereas AR, ER, FAK, P38 PROTACs have been developed against different solid tumors [13, 49, 51, 104] (Table 1).”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [22]
PROTACs consisting of pomalidomide and OTX015 or JQ1 resulted in robust BRD4 degradation at low nanomolar concentrations.
“PROTACs consisting of pomalidomide and OTX015 [84] or JQ1 [85] resulted in robust BRD4 degradation when used at low nanomolar concentrations [84, 85].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [84]
c-Myc levels were strongly depleted, and this depletion lasted longer after washout of the PROTAC than after inhibitor treatment.
“Concomitantly, c-Myc levels were strongly depleted, and this depletion lasted longer after washout of the PROTAC than after inhibitor treatment [84].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [84]
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- Authors
- Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., Hines, J., Winkler, J. D., Crew, A. P., Coleman, K., & Crews, C. M.
- Affiliations
- Arvinas (United States) (US)
- Yale University (US)
- Corresponding author
- Crews, Craig M.
- Venue
- Chemistry & Biology
- Publisher
- Elsevier BV
- Published
- 2015-06
- Volume
- 22
- Issue
- 6
- Pages
- 755-763
- ISSN
- 1074-5521 (ISSN-L)
- PMC
- PMC4475452
- OpenAlex
- W1488181101
- Cited by
- 1,140
- References
- 37
- Citations by year
- 2026: 75 · 2025: 101 · 2024: 135 · 2023: 104 · 2022: 134 · 2021: 118 · 2020: 151 · 2019: 119 · 2018: 77 · 2017: 71 · 2016: 40 · 2015: 10 · 2014: 1
- FWCI
- 29.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Chemistry & Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (AI084140, R01AI084140)
- 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
- BRD4, cereblon, PROTACs, E3 ubiquitin ligase, Burkitt lymphoma, c-Myc, BET proteins, BRD4 inhibitors, protein degradation, apoptosis, cell proliferation inhibition
- MeSH terms
- Acetanilides, Bromodomain Containing Proteins, Azepines, Heterocyclic Compounds, 3-Ring, Humans, Nuclear Proteins, Peptide Hydrolases, Thalidomide, Transcription Factors, Triazoles, Signal Transduction, Proto-Oncogene Proteins c-myc, Apoptosis, Cell Cycle Proteins, Ubiquitin-Protein Ligases, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Cell Proliferation
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