Journal
CHEMICAL & PHARMACEUTICAL BULLETIN
Volume 64, Issue 9, Pages 1378-1383Publisher
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/cpb.c16-00410
Keywords
bromodomain; bromodomain and extra-terminal domain (BET); BRD4; cell differentiation; tumor necrosis factor (TNF)-alpha
Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Japan Society for Promotion of Science, and Platform for Drug Discovery, Informatics, and Structural Life Science
- Grants-in-Aid for Scientific Research [15K08015] Funding Source: KAKEN
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Bromodomains are epigenetic 'readers' of histone acetylation. The first potent bromodomain and extra terminal domain (BET) inhibitors, (+)-JQ1 and I-BET762 (also known as GSK525762), were reported in 2010. Some BET inhibitors are already under clinical trial for the treatment of cancers, but so far, only a few chemical scaffolds are available. We have reported potent N-6-benzoyladenine-based inhibitors of BRD4, a BET family member that serves as a key mediator of transcriptional elongation. Here we present an analysis of the structure activity relationships of these inhibitors. Among the compounds examined, 20, 28 and 29 enhanced all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation and inhibited tumor necrosis factor (TNF)-alpha production by THP-1 cells.
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