RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist.
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...
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2013
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oai:doaj.org-article:e475fa058c6c480b97460e96177ac8f42021-11-18T08:39:39ZRVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist.1932-620310.1371/journal.pone.0083190https://doaj.org/article/e475fa058c6c480b97460e96177ac8f42013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24391744/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Increased 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.Kevin G McLureEmily M GesnerLaura TsujikawaOlesya A KharenkoSarah AttwellEric CampeauSylwia WasiakAdam SteinAndre WhiteEric FontanoRobert K SutoNorman C W WongGregory S WagnerHenrik C HansenPeter R YoungPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 12, p e83190 (2013) |
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DOAJ |
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DOAJ |
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EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Kevin G McLure Emily M Gesner Laura Tsujikawa Olesya A Kharenko Sarah Attwell Eric Campeau Sylwia Wasiak Adam Stein Andre White Eric Fontano Robert K Suto Norman C W Wong Gregory S Wagner Henrik C Hansen Peter R Young RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist. |
| description |
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. |
| format |
article |
| author |
Kevin G McLure Emily M Gesner Laura Tsujikawa Olesya A Kharenko Sarah Attwell Eric Campeau Sylwia Wasiak Adam Stein Andre White Eric Fontano Robert K Suto Norman C W Wong Gregory S Wagner Henrik C Hansen Peter R Young |
| author_facet |
Kevin G McLure Emily M Gesner Laura Tsujikawa Olesya A Kharenko Sarah Attwell Eric Campeau Sylwia Wasiak Adam Stein Andre White Eric Fontano Robert K Suto Norman C W Wong Gregory S Wagner Henrik C Hansen Peter R Young |
| author_sort |
Kevin G McLure |
| title |
RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist. |
| title_short |
RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist. |
| title_full |
RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist. |
| title_fullStr |
RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist. |
| title_full_unstemmed |
RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist. |
| title_sort |
rvx-208, an inducer of apoa-i in humans, is a bet bromodomain antagonist. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/e475fa058c6c480b97460e96177ac8f4 |
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