RVX-208, an Inducer of ApoA-I in Humans, Is a BET Bromodomain Antagonist
| العنوان: | RVX-208, an Inducer of ApoA-I in Humans, Is a BET Bromodomain Antagonist |
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| المؤلفون: | Gregory S. Wagner, Laura Tsujikawa, Emily M. Gesner, Norman C. W. Wong, Robert K. Suto, Eric Fontano, Adam C. Stein, Peter Young, Andre White, Olesya A. Kharenko, Kevin G. McLure, Henrik C. Hansen, Sylwia Wasiak, Sarah Attwell, Eric Campeau |
| المصدر: | PLoS ONE PLoS ONE, Vol 8, Iss 12, p e83190 (2013) |
| بيانات النشر: | Public Library of Science, 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Models, Molecular, Apolipoprotein B, Protein Conformation, Gene Expression, Cell Cycle Proteins, Crystallography, X-Ray, Biochemistry, Epigenesis, Genetic, chemistry.chemical_compound, Drug Discovery, Molecular Cell Biology, Biomacromolecule-Ligand Interactions, RNA, Small Interfering, Multidisciplinary, biology, Chromosome Biology, Reverse cholesterol transport, Nuclear Proteins, Biological activity, Chromatin, Recombinant Proteins, Medicine, lipids (amino acids, peptides, and proteins), Research Article, Biotechnology, BRD4, Protein Structure, Science, Biophysics, RVX 208, Protein Serine-Threonine Kinases, Cell Line, In vivo, Animals, Humans, Binding site, Biology, Quinazolinones, Binding Sites, Apolipoprotein A-I, Proteins, Atherosclerosis, Bromodomain, chemistry, Small Molecules, biology.protein, Hepatocytes, Quinazolines, Transcription Factors |
| الوصف: | 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. |
| اللغة: | English |
| تدمد: | 1932-6203 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::01abcd4c9908ded17455f611bde84ff8 http://europepmc.org/articles/PMC3877016 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....01abcd4c9908ded17455f611bde84ff8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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