title: Stimulation of Hepatic Apolipoprotein A-I Production by Novel Thieno-Triazolodiazepines: Roles of the Classical Benzodiazepine Receptor, PAF Receptor, and Bromodomain Binding.
abstract: Expression and secretion of apolipoprotein A-I (apoA-I) by cultured liver cells can be markedly stimulated by triazolodiazepines (TZDs). It has been shown previously that the thieno-TZD Ro 11-1464 increases plasma levels of apoA-I and in vivomacrophage reverse cholesterol transport in mice. However, these effects were only seen at high doses, at which the compound could act on central benzodiazepine (BZD) receptors or platelet activating factor (PAF) receptors, interfering with its potential utility. In this work, we describe 2 new thieno-TZDs MDCO-3770 and MDCO-3783, both derived from Ro 11-1464. These compounds display the same high efficacy on apoA-I production, metabolic stability, and lack of cytotoxicity in cultured hepatocytes as Ro 11-1464, but they do not bind to the central BZD receptor and PAF receptor. The quinazoline RVX-208 was less efficacious in stimulating apoA-I production and displayed signs of cytotoxicity. Certain TZDs stimulating apoA-I production are now known to be inhibitors of bromodomain (BRD) extra-terminal (BET) proteins BRDT, BRD2, BRD3, and BRD4, and this inhibition was inferred as a main molecular mechanism for their effect on apoA-I expression. We show here that the thieno-TZD (+)-JQ1, a potent BET inhibitor, strongly stimulated apoA-I production in Hep-G2 cells, but that its enantiomer (-)-JQ1, which has no BET inhibitor activity, also showed considerable effect on apoA-I production. MDCO-3770 and MDCO-3783 also inhibited BRD3 and BRD4 in vitro, with potency somewhat below that of (+)-JQ1. We conclude that the effect of thieno-TZDs on apoA-I expression is not due to inhibition of the BZD or PAF receptors and is not completely explained by transcriptional repression by BET proteins.
authors.affiliation: Dybly AG, Basel, Switzerland. ; The Medicines Company (Schweiz) GmbH, Zürich, Switzerland.
authors.forename: Herman J
authors.initials: HJ
authors.lastname: Kempen
authors.affiliation: Dybly AG, Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bellus
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium, Oxford, UK. ; Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, Oxford, UK.
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.affiliation: The Medicines Company (Schweiz) GmbH, Zürich, Switzerland.
authors.forename: Silke
authors.initials: S
authors.lastname: Nicklisch
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium, Oxford, UK. ; Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, Oxford, UK.
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium, Oxford, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Picaud
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium, Oxford, UK. ; Nuffield Department of Clinical Medicine, Target Discovery Institute, Oxford, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
keywords: apolipotein A-I; bromodomain inhibition; thienotriazolodiazepines