RVX-297
目录号 : GC63178
RVX-297 是一种高效、具有口服活性、对 BD2 有选择性的 BET 抑制剂。RVX-297 对 BRD2(BD2)，BRD3(BD2)，BRD4(BD2) 的 IC50 分别为 0.08、0.05、0.02 μM。RVX-297 抑制多种免疫细胞炎症基因的表达。RVX-297 对临床前模型急性炎症和自身免疫的有效。
Cas No.:1044871-04-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >96.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
RVX-297 is a potent, orally active BET bromodomain inhibitor with selectivity for BD2. RVX-297 shows IC50s of 0.08, 0.05, and 0.02 μM for BRD2(BD2), BRD3(BD2), and BRD4(BD2), respectively. RVX-297 suppresses inflammatory gene expression in multiple immune cell types. RVX-297 is effective in acute inflammation and autoimmunity models[1][2].
RVX-297 (1-30 μM; 24 hours) decreases proinflammatory gene expression in synovial fibroblasts[1].RVX-297 displaces BET proteins from the promoters of sensitive genes and disrupted recruitment of active RNA polymerase II, a property shared with pan-BET inhibitors that nonselectively bind BET BDs[1]. RVX-297 reduces gene expression of inflammatory mediators in vitro. RVX-297 suppresses IL-6 gene induction in human U937 macrophages, mouse primary B cells isolated from the spleen, mouse BMDMs, and THP-1 monocytes in a dose-dependent manner. RVX-297 represses IL-1β expression in LPS-stimulated mouse BMDMs, with an IC50 of 0.4-3 μM. RVX-297 inhibits MCP-1 expression in unstimulated human PBMCs with an IC50 of 0.4 μM. RVX-297 inhibits antigen stimulation of T cells and the induction of IL-17 expression[1].
RVX-297 (25-75 mg/kg; p.o.; per day for 6 day) inhibits progression of pathology in the rat collagen-induced arthritis model[1].RVX-297 (75-150 mg/kg) inhibits progression of pathology in the mouse collagen-induced arthritis model[1].RVX-297 suppresses cytokine production in LPS-treated mice[1].
[1]. Jahagirdar R, et al. RVX-297, a BET Bromodomain Inhibitor, Has Therapeutic Effects in Preclinical Models of Acute Inflammation and Autoimmune Disease. Mol Pharmacol. 2017;92(6):694-706.
[2]. Kharenko OA, et al. RVX-297- a novel BD2 selective inhibitor of BET bromodomains. Biochem Biophys Res Commun. 2016;477(1):62-67.
| Cas No. | 1044871-04-6 | SDF | |
| 分子式 | C24H29N3O4 | 分子量 | 423.5 |
| 溶解度 | DMSO : 50 mg/mL (118.06 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.3613 mL | 11.8064 mL | 23.6128 mL |
| 5 mM | 0.4723 mL | 2.3613 mL | 4.7226 mL |
| 10 mM | 0.2361 mL | 1.1806 mL | 2.3613 mL |
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动物平均体重 | g | |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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RVX-297- a novel BD2 selective inhibitor of BET bromodomains
Biochem Biophys Res Commun 2016 Aug 12;477(1):62-67.PMID:27282480DOI:10.1016/j.bbrc.2016.06.021.
Bromodomains are epigenetic readers that specifically bind to the acetyl lysine residues of histones and transcription factors. Small molecule BET bromodomain inhibitors can disrupt this interaction which leads to potential modulation of several disease states. Here we describe the binding properties of a novel BET inhibitor RVX-297 that is structurally related to the clinical compound RVX-208, currently undergoing phase III clinical trials for the treatment of cardiovascular diseases, but is distinctly different in its biological and pharmacokinetic profiles. We report that RVX-297 preferentially binds to the BD2 domains of the BET bromodomain and Extra Terminal (BET) family of protein. We demonstrate the differential binding modes of RVX-297 in BD1 and BD2 domains of BRD4 and BRD2 using X-ray crystallography, and describe the structural differences driving the BD2 selective binding of RVX-297. The isothermal titration calorimetry (ITC) data illustrate the related differential thermodynamics of binding of RVX-297 to single as well as dual BET bromodomains.
RVX-297, a BET Bromodomain Inhibitor, Has Therapeutic Effects in Preclinical Models of Acute Inflammation and Autoimmune Disease
Mol Pharmacol 2017 Dec;92(6):694-706.PMID:28974538DOI:10.1124/mol.117.110379.
Bromodomain (BD) and extra-terminal domain containing proteins (BET) are chromatin adapters that bind acetylated histone marks via two tandem BDs, BD1 and BD2, to regulate gene transcription. BET proteins are involved in transcriptional reprogramming in response to inflammatory stimuli. BET BD inhibitors (BETis) that are nonselective for BD1 or BD2 have recognized anti-inflammatory properties in vitro and counter pathology in models of inflammation or autoimmune disease. Although both BD1 and BD2 bind acetylated histone residues, they may independently regulate the expression of BET-sensitive genes. Here we characterized the ability of RVX-297, a novel orally active BETi with selectivity for BD2, to modulate inflammatory processes in vitro, in vivo, and ex vivo. RVX-297 suppressed inflammatory gene expression in multiple immune cell types in culture. Mechanistically, RVX-297 displaced BET proteins from the promoters of sensitive genes and disrupted recruitment of active RNA polymerase II, a property shared with pan-BETis that nonselectively bind BET BDs. In the lipopolysaccharide model of inflammation, RVX-297 reduced proinflammatory mediators assessed in splenic gene expression and serum proteins. RVX-297 also countered pathology in three rodent models of polyarthritis: rat and mouse collagen-induced arthritis, and mouse collagen antibody-induced arthritis. Further, RVX-297 prevented murine experimental autoimmune encephalomyelitis (a model of human multiple sclerosis) disease development when administered prophylactically and reduced hallmarks of pathology when administered therapeutically. We show for the first time that a BD2-selective BETi maintains anti-inflammatory properties and is effective in preclinical models of acute inflammation and autoimmunity.
Pharmacological Modulation of BET Family in Sepsis
Front Pharmacol 2021 Mar 11;12:642294.PMID:33776776DOI:10.3389/fphar.2021.642294.
The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis 3.0) recommended defining sepsis as a life-threatening organ dysfunction caused by the host's uncontrolled response to infection. The bromodomain and extra-terminal (BET) protein family (such as BRD2, BRD3, and BRD4), an epigenetic regulator of gene transcription, has recently been recognized as a significant septic regulator of inflammation and immune response, including cytokine and chemokine production. Mechanistically, the two N-terminal conserved tandem bromodomains (namely the first bromodomain [BD1] and the second bromodomain [BD2]) favor the binding of BETs to acetylated histones or transcription factors, thereby initiating gene transcription machinery after CycT1 and CDK9 (also known as P-TEFb) are recruited to gene promoters to phosphorylate RNA pol II. Notably, BD1 and BD2 are not functionally redundant because they have different target genes in innate immune cells. Small-molecule BET inhibitors (BETis) for different BDs, such as I-BET, JQ1, I-BET151, apabetalone, RVX-297, and dBET1 have shown promising therapeutic effects in experimental sepsis models. This mini-review summarizes the emerging roles of BETs and the applications of BETis in sepsis, discusses the existing shortcomings of BETis, and introduces possible future research directions in this area.
Deciphering the mechanisms of selective inhibition for the tandem BD1/BD2 in the BET-bromodomain family
Phys Chem Chem Phys 2017 Sep 13;19(35):23934-23941.PMID:28849824DOI:10.1039/c7cp04608a.
The bromodomain and extra terminal domain (BET) family of bromodomains (BRDs) are well-known drug targets for many human diseases. The active pockets of the two tandem bromodomains BD1/BD2 are highly conserved (sequence similarity is about 95%), thus it is of great medical importance and still a significant challenge to develop BD1/BD2 selective inhibitors. A few BD2 selective inhibitors, such as RVX-208 and RVX-297, have been reported recently. However, their selectivity is insufficient for drug discovery, and the molecular basis of the selective inhibition for BD2 over BD1 remains unknown. In this work, by extensive classical molecular dynamics (MD) simulations and hybrid density functional theory/molecular mechanics (DFT/MM) MD simulations, it is for the first time revealed that the selective inhibitory effect towards BD2 is achieved by the distinctive structural dynamics of the ZA-loop ("in/out" conformations) in BD1 and BD2, which originate from the existence of residue Asp144 in BD1 which is replaced by His433 in BD2. Additionally, the more stable inherent H-bond constructed by a conserved D-Y dyad, as well as the stronger π-π stacking interaction formed between His433 and the ligand, are responsible for the higher inhibitory activity of RVX-297 compared to that of RVX-208 in BD2. All these findings should guide further novel inhibitor design and structural modification of validated BD1/BD2 inhibitors to increase the selectivity for BD1/BD2 among the BET family.