RVX-208

Potent BET bromodomain inhibitor CAS# 1044870-39-4

RVX-208

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Chemical structure

RVX-208

3D structure

Chemical Properties of RVX-208

Cas No. 1044870-39-4 SDF Download SDF
PubChem ID 24871506 Appearance Powder
Formula C20H22N2O5 M.Wt 370.4
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Apabetalone; RVX000222
Solubility DMSO : ≥ 33 mg/mL (89.09 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-1H-quinazolin-4-one
SMILES CC1=CC(=CC(=C1OCCO)C)C2=NC(=O)C3=C(C=C(C=C3N2)OC)OC
Standard InChIKey NETXMUIMUZJUTB-UHFFFAOYSA-N
Standard InChI InChI=1S/C20H22N2O5/c1-11-7-13(8-12(2)18(11)27-6-5-23)19-21-15-9-14(25-3)10-16(26-4)17(15)20(24)22-19/h7-10,23H,5-6H2,1-4H3,(H,21,22,24)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of RVX-208

DescriptionRVX-208 is a potent inhibitor of BET bromodomain with IC50 value of 0.51 μM for BD2.
TargetsBD2    
IC500.51 μM     

Protocol

Cell Assay [2]
Huh7 cells are plated at 23,000/well in a 96 well plate in DMEM+10% FBS before allowing to grow overnight. Cells are treated with compounds for 48 h in 0.1% DMSO with or without 5 µM Actinomycin D. U937 cells are differentiated for 3 days in 60 ng/mL PMA, 32,000 cells/well in 96-well format. Cells are then treated with compound in 0.1% DMSO in RPMI media+10% FBS, and after 1 h, lipopolysaccharide is added to the cells at 1 µg/mL for 3 hours[2].

Animal Administration [3]
Mice[3] Seven to eight week old male ApoE-/- mice are used. Based on the body weight and lipid values, mice are divided into 2 groups (n=12): group 1, vehicle; and group 2, test agent, RVX-208. Mice are then switched to Western diet (0.15% cholesterol and 42% calories from fat) and concurrently treated orally by gavage with either vehicle or the test agent, RVX-208 (150 mg/kg/dose b.i.d) for 12 weeks. After 6 week of treatment, an interim blood draw is done to monitor serum lipid levels. After 12 weeks of treatment mice are sacrificed to measure blood lipid parameters, aortic lesion, and liver and aortic RNA. Eight mice are used for enface (aortic plaque) analysis, 4 mice for tissue collection for mRNA and all 12 mice used for aortic sinus lesion area measurement.

References:
[1]. Picaud S, et al. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc Natl Acad Sci U S A. 2013 Dec 3;110(49):19754-9. [2]. McLure KG, et al. RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist. PLoS One. 2013 Dec 31;8(12):e83190. [3]. Jahagirdar R, et al. A novel BET bromodomain inhibitor, RVX-208, shows reduction of atherosclerosis in hyperlipidemic ApoE deficient mice. Atherosclerosis. 2014 Sep;236(1):91-100.

RVX-208 Dilution Calculator

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Preparing Stock Solutions of RVX-208

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.6998 mL 13.4989 mL 26.9978 mL 53.9957 mL 67.4946 mL
5 mM 0.54 mL 2.6998 mL 5.3996 mL 10.7991 mL 13.4989 mL
10 mM 0.27 mL 1.3499 mL 2.6998 mL 5.3996 mL 6.7495 mL
50 mM 0.054 mL 0.27 mL 0.54 mL 1.0799 mL 1.3499 mL
100 mM 0.027 mL 0.135 mL 0.27 mL 0.54 mL 0.6749 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on RVX-208

RVX-208 is a potent inhibitor of bromodomain with IC50 values of 0.51 and 87 μM for BD2 and BD1, respectively [1].

Bromodomains (BRDs) are protein-interaction modules that bind to ε-N-acetylated lysine-containing proteins. BRDs act as effector domains of chromatin-modifying enzymes, transcriptional regulators and chromatin modulators [1].

RVX-208 is a potent second BET bromodomains inhibitor. RVX-208 exhibited affinity with KD values of 0.194 and 4.06 for BD2 and BD1, respectively. RVX-208 bound to the acetyl-lysine binding pocket in a peptide-competitive way [1]. In HepG2 cells, RVX-208 induced messenger ribonucleic acid and protein synthesis of apolipoprotein (apo)A-I [2]. RVX-208 induced ApoA-I mRNA mediated by BRD4 [3].

In African green monkeys, RVX-208 increased serum HDL-C and apoA-I levels by 97% and 60%, respectively. Also, RVX-208 increased the levels of pre-β1-LpA-I, α1-LpA-I HDL-subparticles, adenosine triphosphate binding cassette G1, adenosine triphosphate binding cassette AI and cholesterol efflux [2]. In hyperlipidemic apoE(-/-) mice, RVX-208 (150?mg/kg) significantly inhibited aortic lesion. Also, RVX-208 increased HDL-C and reduced LDL-C and proinflammatory cytokines [4].

References:
[1].  Picaud S, Wells C, Felletar I, et al. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc Natl Acad Sci U S A, 2013, 110(49): 19754-19759.
[2].  Bailey D, Jahagirdar R, Gordon A, et al. RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J Am Coll Cardiol, 2010, 55(23): 2580-2589.
[3].  McLure KG, Gesner EM, Tsujikawa L, et al. RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist. PLoS One, 2013, 8(12): e83190.
[4].  Jahagirdar R, Zhang H, Azhar S, et al. A novel BET bromodomain inhibitor, RVX-208, shows reduction of atherosclerosis in hyperlipidemic ApoE deficient mice. Atherosclerosis, 2014, 236(1): 91-100.

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References on RVX-208

Data on gene and protein expression changes induced by apabetalone (RVX-208) in ex vivo treated human whole blood and primary hepatocytes.[Pubmed:27570805]

Data Brief. 2016 Jul 29;8:1280-8.

Apabetalone (RVX-208) inhibits the interaction between epigenetic regulators known as bromodomain and extraterminal (BET) proteins and acetyl-lysine marks on histone tails. Data presented here supports the manuscript published in Atherosclerosis "RVX-208, a BET-inhibitor for Treating Atherosclerotic Cardiovascular Disease, Raises ApoA-I/HDL and Represses Pathways that Contribute to Cardiovascular Disease" (Gilham et al., 2016) [1]. It shows that RVX-208 and a comparator BET inhibitor (BETi) JQ1 increase mRNA expression and production of apolipoprotein A-I (ApoA-I), the main protein component of high density lipoproteins, in primary human and African green monkey hepatocytes. In addition, reported here are gene expression changes from a microarray-based analysis of human whole blood and of primary human hepatocytes treated with RVX-208.

Effects of the BET-inhibitor, RVX-208 on the HDL lipidome and glucose metabolism in individuals with prediabetes: A randomized controlled trial.[Pubmed:27173469]

Metabolism. 2016 Jun;65(6):904-14.

AIMS: High-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) can modulate glucose metabolism through multiple mechanisms. This study determined the effects of a novel bromodomain and extra-terminal (BET) inhibitor (RVX-208) and putative apoA-I inducer on lipid species contained within HDL (HDL lipidome) and glucose metabolism. MATERIALS AND METHODS: Twenty unmedicated males with prediabetes received 100mg b.i.d. RVX-208 and placebo for 29-33days separated by a wash-out period in a randomized, cross-over design trial. Plasma HDL-cholesterol and apoA-I were assessed as well as lipoprotein particle size and distribution using NMR spectroscopy. An oral glucose tolerance test (OGTT) protocol with oral and infused stable isotope tracers was employed to assess postprandial plasma glucose, indices of insulin secretion and insulin sensitivity, glucose kinetics and lipolysis. Whole plasma and HDL lipid profiles were measured using mass spectrometry. RESULTS: RVX-208 treatment for 4weeks increased 6 sphingolipid and 4 phospholipid classes in the HDL lipidome (pRVX-208 treatment. In response to a glucose load, after RVX-208 treatment, plasma glucose peaked at a similar level to placebo, but 30min later with a more sustained elevation (treatment effect, P=0.003). There was a reduction and delay in total (P=0.001) and oral (P=0.003) glucose rates of appearance in plasma and suppression of endogenous glucose production (P=0.014) after RVX-208 treatment. The rate of glucose disappearance was also lower following RVX-208 (P=0.016), with no effect on glucose oxidation or total glucose disposal. CONCLUSIONS: RVX-208 increased 10 lipid classes in the plasma HDL fraction, without altering the concentrations of either apoA-I or HDL-cholesterol (HDL-C). RVX-208 delayed and reduced oral glucose absorption and endogenous glucose production, with plasma glucose maintained via reduced peripheral glucose disposal. If sustained, these effects may protect against the development of type 2 diabetes.

RVX-208, a BET-inhibitor for treating atherosclerotic cardiovascular disease, raises ApoA-I/HDL and represses pathways that contribute to cardiovascular disease.[Pubmed:26868508]

Atherosclerosis. 2016 Apr;247:48-57.

High density lipoproteins (HDL), through activity of the main protein component apolipoprotein A-I (ApoA-I), can reduce the risk of cardiovascular disease (CVD) by removing excess cholesterol from atherosclerotic plaque. In this study, we demonstrate that the bromodomain and extraterminal domain (BET) inhibitor RVX-208 increases ApoA-I gene transcription and protein production in human and primate primary hepatocytes. Accordingly, RVX-208 also significantly increases levels of ApoA-I, HDL-associated cholesterol, and HDL particle number in patients who received the compound in recently completed phase 2b trials SUSTAIN and ASSURE. Moreover, a post-hoc analysis showed lower instances of major adverse cardiac events in patients receiving RVX-208. To understand the effects of RVX-208 on biological processes underlying cardiovascular risk, we performed microarray analyses of human primary hepatocytes and whole blood treated ex vivo. Overall, data showed that RVX-208 raises ApoA-I/HDL and represses pro-inflammatory, pro-atherosclerotic and pro-thrombotic pathways that can contribute to CVD risk.

Description

Apabetalone (RVX-208) is an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. The IC50s are 87±10 μM and 0.51±0.041 μM for BD1 and BD2, respectively.

Keywords:

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