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Selective inhibition of BET bromodomains
Open accessAbstract
Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.
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“Previous studies have reported that SALL4 is an IMiD-dependent CRL4CRBN substrate (Donovan et al, 2018; Filippakopoulos et al, 2010).”
From Targeting transcription factors through an IMiD independent zinc finger domain (2025) · cites this paper as Filippakopoulos et al, 2010
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Self-citation
Metadata
- Authors
- Filippakopoulos, P., Qi, J., Picaud, S., Shen, Y., Smith, W. B., Fedorov, O., Morse, E. M., Keates, T., Hickman, T. T., Felletar, I., Philpott, M., Munro, S., McKeown, M. R., Wang, Y., Christie, A. L., West, N., Cameron, M. J., Schwartz, B., Heightman, T. D., La Thangue, N., French, C. A., Wiest, O., Kung, A. L., Knapp, S., & Bradner, J. E.
- Affiliations
- University of Oxford (GB)
- Harvard University (US)
- University of Notre Dame (US)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Corresponding author
- Knapp, Stefan
- Bradner, James E.
- ORCID
- Venue
- Nature
- Published
- 2010-09-24
- Volume
- 468
- Issue
- 7327
- Pages
- 1067-1073
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3010259
- OpenAlex
- W2041535798
- Cited by
- 4,262
- References
- 42
- Citations by year
- 2026: 217 · 2025: 307 · 2024: 304 · 2023: 307 · 2022: 309 · 2021: 323 · 2020: 340 · 2019: 323 · 2018: 303 · 2017: 306 · 2016: 334 · 2015: 279 · 2014: 246 · 2013: 177 · 2012: 117
- FWCI
- 48.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Oxford University Research Archive (ORA) (University of Oxford) (submittedVersion)
- Funders
- Wellcome Trust
- Cancer Research UK (13058)
- U.S. Public Health Service (T32-075762)
- Canadian Institutes of Health Research
- National Cancer Institute (K08CA128972)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- BET inhibitors, JQ1, BRD4, epigenetic reader protein, protein-protein interaction inhibition, squamous cell carcinoma, histone acetylation, co-crystal structure, chemical probes, transcriptional regulation
- MeSH terms
- Bromodomain Containing Proteins, Amino Acid Sequence, Animals, Azirines, Binding Sites, Carcinoma, Squamous Cell, Cell Differentiation, Chromatin, Dihydropyridines, Female, Humans, Mice, Nude, Models, Molecular, Molecular Sequence Data, Nuclear Proteins, Protein Binding, Recombinant Proteins, Skin Neoplasms, Stereoisomerism, Transcription Factors, Sequence Alignment, Protein Structure, Tertiary, Cell Cycle Proteins, Cell Line, Tumor, Cell Proliferation, Mice
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