期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 49, 页码 19754-19759出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1310658110
关键词
small molecule inhibitor; epigenetics; microarray; ApoA1
资金
- Structural Genomics Consortium, a registered charity [1097737]
- Canadian Institutes for Health Research
- Canada Foundation for Innovation
- Genome Canada
- GlaxoSmithKline
- Pfizer
- Eli Lilly
- Takeda
- AbbVie
- Novartis Research Foundation
- Ontario Ministry of Research and Innovation
- Wellcome Trust [092809/Z/10/Z]
- Wellcome Trust Career Development Fellowship [095751/Z/11/Z]
Bromodomains have emerged as attractive candidates for the development of inhibitors targeting gene transcription. Inhibitors of the bromo and extraterminal (BET) family recently showed promising activity in diverse disease models. However, the pleiotropic nature of BET proteins regulating tissue-specific transcription has raised safety concerns and suggested that attempts should be made for domain-specific targeting. Here, we report that RVX-208, a compound currently in phase II clinical trials, is a BET bromodomain inhibitor specific for second bromodomains (BD2s). Cocrystal structures revealed binding modes of RVX-208 and its synthetic precursor, and fluorescent recovery after photobleaching demonstrated that RVX-208 displaces BET proteins from chromatin. However, gene-expression data showed that BD2 inhibition only modestly affects BET-dependent gene transcription. Our data demonstrate the feasibility of specific targeting within the BET family resulting in different transcriptional outcomes and high-light the importance of BD1 in transcriptional regulation.
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