Abstract
Increased synthesis of Apolipoprotein A-I (ApoA-I) and HDL is believed to provide a new approach to treating atherosclerosis through the stimulation of reverse cholesterol transport. RVX-208 increases the production of ApoA-I in hepatocytes in vitro, and in vivo in monkeys and humans, which results in increased HDL-C, but the molecular target was not previously reported. Using binding assays and X-ray crystallography, we now show that RVX-208 selectively binds to bromodomains of the BET (Bromodomain and Extra Terminal) family, competing for a site bound by the endogenous ligand, acetylated lysine, and that this accounts for its pharmacological activity. siRNA experiments further suggest that induction of ApoA-I mRNA is mediated by BET family member BRD4. These data indicate that RVX-208 increases ApoA-I production through an epigenetic mechanism and suggests that BET inhibition may be a promising new approach to the treatment of atherosclerosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apolipoprotein A-I / biosynthesis*
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Apolipoprotein A-I / genetics
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Atherosclerosis / drug therapy
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Atherosclerosis / metabolism
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Binding Sites
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Cell Cycle Proteins
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Cell Line
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Crystallography, X-Ray
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Epigenesis, Genetic / drug effects
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Humans
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Models, Molecular
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Nuclear Proteins / antagonists & inhibitors*
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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics
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Protein Conformation
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / genetics
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Quinazolines / chemistry
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Quinazolines / pharmacology*
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Quinazolinones
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RNA, Small Interfering / genetics
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / chemistry
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Transcription Factors / genetics
Substances
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Apolipoprotein A-I
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BRD2 protein, human
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BRD4 protein, human
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Cell Cycle Proteins
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Nuclear Proteins
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Quinazolines
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Quinazolinones
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RNA, Small Interfering
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Recombinant Proteins
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Transcription Factors
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apabetalone
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Protein Serine-Threonine Kinases
Grants and funding
This work was funded by Resverlogix Corp,
www.resverlogix.com. EMG received salary support from Alberta Innovates
www.albertatechfutures.ca. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.