Abstract
Pan-bromodomain and extra terminal (BET) inhibitors interact equipotently with all eight bromodomains of the BET family of proteins. They have shown profound efficacy in vitro and in vivo in oncology and immunomodulatory models, and a number of them are currently in clinical trials where significant safety signals have been reported. It is therefore important to understand the functional contribution of each bromodomain to assess the opportunity to tease apart efficacy and toxicity. This article discloses the in vitro and cellular activity profiles of GSK789, a potent, cell-permeable, and highly selective inhibitor of the first bromodomains of the BET family.
MeSH terms
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ATPases Associated with Diverse Cellular Activities / antagonists & inhibitors
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ATPases Associated with Diverse Cellular Activities / metabolism
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / metabolism
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Anti-Inflammatory Agents / pharmacology
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Binding Sites
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Crystallography, X-Ray
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / metabolism
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Half-Life
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Humans
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Molecular Dynamics Simulation
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Naphthyridines / chemistry*
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Naphthyridines / metabolism
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Naphthyridines / pharmacology
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Protein Domains
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Quinolones / chemistry
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Quinolones / metabolism
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Quinolones / pharmacology
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / metabolism
Substances
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Anti-Inflammatory Agents
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BRD4 protein, human
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Cell Cycle Proteins
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DNA-Binding Proteins
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Naphthyridines
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Quinolones
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Transcription Factors
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ATAD2 protein, human
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ATPases Associated with Diverse Cellular Activities