Abstract
In recent years, inhibition of the interaction between the bromodomain and extra-terminal domain (BET) family of chromatin adaptors and acetyl-lysine residues on chromatin has emerged as a promising approach to regulate the expression of important disease-relevant genes, including MYC, BCL-2, and NF-κB. Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological malignancies (CPI-0610).
MeSH terms
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Animals
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Azepines / chemistry*
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Azepines / pharmacokinetics
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Azepines / pharmacology
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Azepines / therapeutic use*
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Cell Cycle Proteins
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Cell Line, Tumor
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Clinical Trials as Topic
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Dogs
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Gene Expression Regulation, Neoplastic / drug effects*
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Genes, myc / drug effects
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Humans
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Leukemia, Myeloid, Acute / drug therapy*
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Leukemia, Myeloid, Acute / genetics
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Leukemia, Myeloid, Acute / metabolism
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Mice
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Nuclear Proteins / antagonists & inhibitors*
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Nuclear Proteins / chemistry
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Nuclear Proteins / metabolism
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Proto-Oncogene Proteins c-myc / genetics
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Rats
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / chemistry
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Transcription Factors / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Azepines
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BRD4 protein, human
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Cell Cycle Proteins
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Nuclear Proteins
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Proto-Oncogene Proteins c-myc
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Transcription Factors