title: RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist.
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.
authors.affiliation: Resverlogix Corp., Calgary, Alberta, Canada, or San Francisco, California, United States of America.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: McLure
authors.affiliation: Resverlogix Corp., Calgary, Alberta, Canada, or San Francisco, California, United States of America.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Gesner
authors.affiliation: Resverlogix Corp., Calgary, Alberta, Canada, or San Francisco, California, United States of America.
authors.forename: Laura
authors.initials: L
authors.lastname: Tsujikawa
authors.affiliation: Resverlogix Corp., Calgary, Alberta, Canada, or San Francisco, California, United States of America.
authors.forename: Olesya A
authors.initials: OA
authors.lastname: Kharenko
authors.affiliation: Resverlogix Corp., Calgary, Alberta, Canada, or San Francisco, California, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Attwell
authors.affiliation: Resverlogix Corp., Calgary, Alberta, Canada, or San Francisco, California, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Campeau
authors.affiliation: Resverlogix Corp., Calgary, Alberta, Canada, or San Francisco, California, United States of America.
authors.forename: Sylwia
authors.initials: S
authors.lastname: Wasiak
authors.affiliation: Xtal BioStructures Inc., Natick, Maryland, United States of America.
authors.forename: Adam
authors.initials: A
authors.lastname: Stein
authors.affiliation: Xtal BioStructures Inc., Natick, Maryland, United States of America.
authors.forename: Andre
authors.initials: A
authors.lastname: White
authors.affiliation: Xtal BioStructures Inc., Natick, Maryland, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Fontano
authors.affiliation: Xtal BioStructures Inc., Natick, Maryland, United States of America.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Suto
authors.affiliation: Resverlogix Corp., Calgary, Alberta, Canada, or San Francisco, California, United States of America.
authors.forename: Norman C W
authors.initials: NC
authors.lastname: Wong
authors.affiliation: Resverlogix Corp., Calgary, Alberta, Canada, or San Francisco, California, United States of America.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Wagner
authors.affiliation: Resverlogix Corp., Calgary, Alberta, Canada, or San Francisco, California, United States of America.
authors.forename: Henrik C
authors.initials: HC
authors.lastname: Hansen
authors.affiliation: Resverlogix Corp., Calgary, Alberta, Canada, or San Francisco, California, United States of America.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Young
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism; D001665:Binding Sites; D018797:Cell Cycle Proteins; D002460:Cell Line; D018360:Crystallography, X-Ray; D044127:Epigenesis, Genetic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D052999:Quinazolinones; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D000092468:Bromodomain Containing Proteins
chemical_list: D016632:Apolipoprotein A-I; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011799:Quinazolines; D052999:Quinazolinones; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C441289:BRD4 protein, human; C000628794:apabetalone