Abstract
The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma and other cancers.
MeSH terms
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Animals
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / pharmacokinetics
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Anti-Inflammatory Agents / pharmacology
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Apolipoprotein A-I / biosynthesis
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Benzodiazepines / chemical synthesis
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Benzodiazepines / pharmacokinetics
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Benzodiazepines / pharmacology*
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Cell Cycle Proteins
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Dogs
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Epigenesis, Genetic
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Humans
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Macaca fascicularis
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Mice
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Models, Molecular
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Nuclear Proteins / antagonists & inhibitors*
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Permeability
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Protein Structure, Tertiary
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Rats
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Stereoisomerism
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Structure-Activity Relationship
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Transcription Factors / antagonists & inhibitors*
Substances
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APOA1 protein, human
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Anti-Inflammatory Agents
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Antineoplastic Agents
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Apolipoprotein A-I
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BRD4 protein, human
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Cell Cycle Proteins
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Nuclear Proteins
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Transcription Factors
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Benzodiazepines
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molibresib