Abstract
The bromodomain and extra-terminal (BET) family of proteins, consisting of the bromodomains containing protein 2 (BRD2), BRD3, BRD4, and the testis-specific BRDT, are key epigenetic regulators of gene transcription and has emerged as an attractive target for anticancer therapy. Herein, we describe the discovery of a novel potent BET bromodomain inhibitor, using a systematic structure-based approach focused on improving potency, metabolic stability, and permeability. The optimized dimethylisoxazole aryl-benzimidazole inhibitor exhibited high potency towards BRD4 and related BET proteins in biochemical and cell-based assays and inhibited tumor growth in two proof-of-concept preclinical animal models.
Keywords:
Antitumor; BET proteins; Bromodomain inhibitor; Epigenetic readers.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Administration, Oral
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Animals
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Benzimidazoles / chemistry
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Benzimidazoles / metabolism
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Benzimidazoles / pharmacology*
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Biological Availability
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Drug Discovery*
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Humans
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Isoxazoles / administration & dosage
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Isoxazoles / chemistry
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Isoxazoles / metabolism
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Isoxazoles / pharmacology*
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Mice
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Molecular Structure
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / metabolism
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Multiple Myeloma / pathology
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Protein Domains / drug effects
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Structure-Activity Relationship
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / metabolism
Substances
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Benzimidazoles
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Isoxazoles
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Transcription Factors