Abstract
TRIM24 is a transcriptional regulator as well as an E3 ubiquitin ligase. It is overexpressed in diverse tumors, and high expression levels have been linked to poor prognosis in breast cancer patients. TRIM24 contains a PHD/bromodomain offering the opportunity to develop protein interaction inhibitors that target this protein interaction module. Here we identified potent acetyl-lysine mimetic benzimidazolones TRIM24 bromodomain inhibitors. The best compound of this series is a selective BRPF1B/TRIM24 dual inhibitor that bound with a KD of 137 and 222 nM, respectively, but exerted good selectivity over other bromodomains. Cellular activity of the inhibitor was demonstrated using FRAP assays as well as cell viability data.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / metabolism
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Benzimidazoles / chemistry*
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Benzimidazoles / pharmacology*
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Carrier Proteins / antagonists & inhibitors*
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Carrier Proteins / chemistry
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Carrier Proteins / metabolism
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Cell Line, Tumor
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Crystallography, X-Ray
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DNA-Binding Proteins
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Humans
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Lysine / analogs & derivatives
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Models, Molecular
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Molecular Docking Simulation
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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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Protein Structure, Tertiary / drug effects
Substances
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Adaptor Proteins, Signal Transducing
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BRPF1 protein, human
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Benzimidazoles
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Carrier Proteins
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DNA-Binding Proteins
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Nuclear Proteins
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TRIM24 protein, human
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benzimidazolone
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Lysine