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MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53
Open accessPublished version of a preprint
Abstract
Although the number of proteins effectively targeted for posttranslational degradation by PROTAC has grown steadily, the number of E3 ligases successfully exploited to accomplish this has been limited to the few for which small-molecule ligands have been discovered. Although the E3 ligase MDM2 is bound by the nutlin class of small-molecule ligands, there are few nutlin-based PROTAC. Because a nutlin-based PROTAC should both knockdown its target protein and upregulate the tumor suppressor p53, we examined the ability of such a PROTAC to decrease cancer cell viability. A nutlin-based, BRD4-degrading PROTAC, A1874, was able to degrade its target protein by 98% with nanomolar potency. Given the complementary ability of A1874 to stabilize p53, we discovered that the nutlin-based PROTAC was more effective in inhibiting proliferation of many cancer cell lines with wild-type p53 than was a corresponding VHL-utilizing PROTAC with similar potency and efficacy to degrade BRD4. This is the first report of a PROTAC in which the E3 ligase ligand and targeting warhead combine to exert a synergistic antiproliferative effect. Our study highlights the untapped potential that may be unlocked by expanding the repertoire of E3 ligases that can be recruited by PROTAC. Significance: These findings present the first BRD4-targeting MDM2-based PROTAC that possesses potent, distinct, and synergistic biological activities associated with both ends of this heterobifunctional molecule.
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“This PROTAC, A1874, degraded BRD4 almost completely in HCT116 cells at 100 nM within 24 h.”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [68]
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“It was recently shown that a MDM2-based PROTAC could synergistically combine a catalytic mechanism of action, via degradation of a neo-substrate, and an occupancy-based effect, via competition with, and stabilization of, the endogenous substrate p53 (ref. 60 ).”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [60]
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Selective inhibition of BET bromodomains
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Self-citationIdentification of a Primary Target of Thalidomide Teratogenicity
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Catalytic in vivo protein knockdown by small-molecule PROTACs
Bondeson, D. P., Mares, A., Smith, I. E. D., Ko, E., Campos, S., Miah, A. H., Mulholland, K. E., Routly, N., Buckley, D. L., Gustafson, J. L., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1858 · Cited by 1,356
Self-citationStructural basis of PROTAC cooperative recognition for selective protein degradation
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Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4
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Self-citationAnalysis of drug combinations: current methodological landscape
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Metadata
- Authors
- Hines, J., Lartigue, S., Dong, H., Qian, Y., & Crews, C. M.
- Affiliations
- Yale University (US)
- Arvinas (United States) (US)
- Corresponding author
- Crews, Craig M.
- Venue
- Cancer Research
- Published
- 2019-01-01
- Volume
- 79
- Issue
- 1
- Pages
- 251-262
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC6318015
- OpenAlex
- W2898621430
- Cited by
- 348
- References
- 56
- Citations by year
- 2026: 30 · 2025: 49 · 2024: 52 · 2023: 41 · 2022: 60 · 2021: 45 · 2020: 45 · 2019: 25
- FWCI
- 10.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NCI (R50 CA211252)
- NIH (R35 CA197589)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- PROTACs, MDM2, BRD4 degradation, p53 stabilization, nutlin, E3 ubiquitin ligase, VHL, antiproliferative activity, drug synergy, heterobifunctional molecules, tumor cell proliferation
- MeSH terms
- Bromodomain Containing Proteins, Drug Synergism, Fibrinolytic Agents, Humans, Neoplasms, Nuclear Proteins, Peptides, Transcription Factors, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Cell Cycle Proteins, Cell Proliferation, Proto-Oncogene Proteins c-mdm2, Protein Stability, Proteolysis
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