2. Academic Validation
  3. RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist

RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist

  • PLoS One. 2013 Dec 31;8(12):e83190. doi: 10.1371/journal.pone.0083190.
Kevin G McLure 1,  Emily M Gesner 1,  Laura Tsujikawa 1,  Olesya A Kharenko 1,  Sarah Attwell 1,  Eric Campeau 1,  Sylwia Wasiak 1,  Adam Stein 2,  Andre White 2,  Eric Fontano 2,  Robert K Suto 2,  Norman C W Wong 1,  Gregory S Wagner 1,  Henrik C Hansen 1,  Peter R Young 1
Affiliations

Affiliations

  • 1 Resverlogix Corp., Calgary, Alberta, Canada, or San Francisco, California, United States of America.
  • 2 Xtal BioStructures Inc., Natick, Maryland, United States of America.
PMID: 24391744 DOI: 10.1371/journal.pone.0083190
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.

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