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Rvx 208.

ABSTRACT: RVX 208 (RVX-208; RVX000222) is a first-in-class novel small molecule in development by Resverlogix Corporation for acute coronary syndromes, atherosclerosis and Alzheimer disease. It increases the levels of apolipoprotein A1 and high-density lipoprotein cholesterol, thereby potentially reducing the risk for cardiovascular disease. This review discusses the key development milestones and therapeutic trials of this drug. This summary has been extracted from Wolters Kluwer's R&D Insight drug pipeline database. R&D Insight tracks and evaluates drug development worldwide through the entire development process, from discovery, through pre-clinical and clinical studies to market launch. This is an open access article published under the terms of the Creative Commons License "Attribution-NonCommercial-NoDerivative 3.0" (http://creativecommons.org/licenses/by-nc-nd/3.0/) which permits non-commercial use, distribution, and reproduction, provided the original work is properly cited and not altered.

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PROVIDER: S-EPMC3585949 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundApabetalone (RVX-208) is a bromodomain and extraterminal protein inhibitor (BETi) that in phase II trials reduced the relative risk (RR) of major adverse cardiac events (MACE) in patients with cardiovascular disease (CVD) by 44% and in diabetic CVD patients by 57% on top of statins. A phase III trial, BETonMACE, is currently assessing apabetalone's ability to reduce MACE in statin-treated post-acute coronary syndrome type 2 diabetic CVD patients with low high-density lipoprotein C. The leading cause of MACE is atherosclerosis, driven by dysfunctional lipid metabolism and chronic vascular inflammation (VI). In vitro studies have implicated the BET protein BRD4 as an epigenetic driver of inflammation and atherogenesis, suggesting that BETi may be clinically effective in combating VI. Here, we assessed apabetalone's ability to regulate inflammation-driven gene expression and cell adhesion in vitro and investigated the mechanism by which apabetalone suppresses expression. The clinical impact of apabetalone on mediators of VI was assessed with proteomic analysis of phase II CVD patient plasma.ResultsIn vitro, apabetalone prevented inflammatory (TNFα, LPS, or IL-1β) induction of key factors that drive endothelial activation, monocyte recruitment, adhesion, and plaque destabilization. BRD4 abundance on inflammatory and adhesion gene promoters and enhancers was reduced by apabetalone. BRD2-4 degradation by MZ-1 also prevented TNFα-induced transcription of monocyte and endothelial cell adhesion molecules and inflammatory mediators, confirming BET-dependent regulation. Transcriptional regulation by apabetalone translated into a reduction in monocyte adhesion to an endothelial monolayer. In a phase II trial, apabetalone treatment reduced the abundance of multiple VI mediators in the plasma of CVD patients (SOMAscan® 1.3 k). These proteins correlate with CVD risk and include adhesion molecules, cytokines, and metalloproteinases. Ingenuity® Pathway Analysis (IPA®) predicted that apabetalone inhibits pro-atherogenic regulators and pathways and prevents disease states arising from leukocyte recruitment.ConclusionsApabetalone suppressed gene expression of VI mediators in monocytes and endothelial cells by inhibiting BET-dependent transcription induced by multiple inflammatory stimuli. In CVD patients, apabetalone treatment reduced circulating levels of VI mediators, an outcome conducive with atherosclerotic plaque stabilization and MACE reduction. Inhibition of inflammatory and adhesion molecule gene expression by apabetalone is predicted to contribute to MACE reduction in the phase III BETonMACE trial.

Project description:Bromodomains have emerged as attractive candidates for the development of inhibitors targeting gene transcription. Inhibitors of the bromo-and-extra-terminal (BET) family recently showed promising activity in diverse disease models. However, the pleiotropic nature of BET proteins regulating tissue specific transcription has raised safety concerns and suggested that attempts should be made for domain-specific targeting. Here we report that RVX-208, a compound currently in phase II clinical trials, is a BET bromodomain inhibitor specific for second bromodomains (BD2). Co-crystal structures revealed binding modes of RVX-208 and its synthetic precursor and fluorescent recovery after photobleaching demonstrated that RVX-208 displaces BET proteins from chromatin. However, gene expression data showed that BD2 inhibition only modestly affects BET-dependent gene transcription. Our data demonstrate the feasibility of specific targeting within the BET family resulting in different transcriptional outcomes and highlight the importance of BD1 in transcriptional regulation HepG2 Cells were treated with eitther DMSO or 0.5uM JQ1 or 5uM RVX-208. Three samples per condition, total of nine samples. Inhbitor treatment was carried out for 4h before RNA was extracted. HepG2 cells (ATCC: HB-8065) were maintained in M-NM-1-MEM (Cat.#BE12-169F; BioWhittaker) supplemented with 10 % heat-inactivated foetal calf serum (PAA #A15-152), non-essential amino acids (Cat. #M7145; Sigma), glutamine (Cat.#M11-004; PAA), and vitamins (Cat.#M6895; Sigma). Cells were grown at 37 M-BM-0C in a humidified cabinet at 5 % CO2 (Heraeus Function Line). For experiments, cells were seeded the day prior to treatment at 2x105/ml. Treatments were performed for 4 h so that a final concentration of 0.1 % DMSO (Cat.#D1435; Sigma) was achieved. At harvest, cells were washed once with PBS (Cat.#H15-002; PAA), and lysed in situ using RLT buffer supplemented with 10 M-NM-<l/ml M-NM-2-mercaptoethanol (Cat.#M7522; Sigma). Total RNA was extracted and prepared using RNeasy columns (Cat.#74106 plus; Qiagen) including a Qia shredding step (Cat.#79656; Qiagen) and an on-column DNAse digestion (Cat.#EN0521; Fermentas), according to the manufacturerM-bM-^@M-^Ys instructions. The resulting RNA was quantified and quality controlled using a Nanodrop spectrophotometer (model ND1000; Thermo Fisher). RNA integrity was assessed on a BioAnalyzer (model G2938C; Agilent Laboratories, USA) and all samples had a RNA Integrity Number (RIN) M-bM-^IM-% 9. Labelled sense ssDNA for hybridization was generated from 200 ng starting RNA with the Ambion WT expression kit (Cat.#4411973; Ambion) and the Affymetrix GeneChip WT Terminal Labelling and Controls Kit (Cat.#901525; Affymetrix) according to the manufacturerM-bM-^@M-^Ys instructions. The distribution of fragmented sense ssDNA lengths was measured on the BioAnalyser. The fragmented ssDNA was labelled and hybridized for 17 hours at 45 M-BM-0C on the Affymetrix GeneChip Human Gene 1.0 ST Array (Affymetrix). Chips were processed on an Affymetrix GeneChip Fluidics Station 450 and Scanner 3000 and the affymetrix Command Console (v.3.2.4; Affymetrix) was used to generate CEL files.

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Rvx 208.

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