RVX-208, an Inducer of ApoA-I in Humans, is a BET Bromodomain Antagonist

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2014 Jan 7

PMID 24391744

Citations 78

Authors

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

Affiliations

Soon will be listed here.

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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