Cited by 4,262Protein Degradation and InhibitorsChromatin Remodeling and CancerEpigenetics and DNA Methylation

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Selective inhibition of BET bromodomains

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Filippakopoulos, Panagis, Qi, Jun, Picaud, Sarah, Shen, Yao, Smith, William B., Fedorov, Oleg, Morse, Elizabeth M., Keates, Tracey, Hickman, Tyler T., Felletar, Ildiko, Philpott, Martin, Munro, Shonagh, McKeown, Michael R., Wang, Yuchuan, Christie, Amanda L., West, Nathan, Cameron, Michael J., Schwartz, Brian, Heightman, Tom D., La Thangue, Nicholas, French, Christopher A., Wiest, Olaf, Kung, Andrew L., Knapp, Stefan, Bradner, James E.·2010·Nature

DOI 10.1038/nature09504PMC PMC3010259

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Abstract

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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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: Filippakopoulos, Panagis
Qi, Jun
Picaud, Sarah
Shen, Yao
Fedorov, Oleg
Hickman, Tyler T.
Philpott, Martin
Munro, Shonagh
McKeown, Michael R.
Wang, Yuchuan
Schwartz, Brian
Heightman, Tom D.
French, Christopher A.
Wiest, Olaf
Kung, Andrew L.
Knapp, Stefan
Bradner, James E.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2010-09-24
Volume: 468
Issue: 7327
Pages: 1067-1073
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature09504
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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