| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg |
|
||
| Other Sizes |
|
Purity: ≥98%
SR9011 is a novel and potent synthetic REV-ERBα/β agonist with IC50 values of 790 nM and 560 nM for REV-ERBα and REV-ERBβ, respectively. Synchronizing rhythms of behaviour and metabolic processes is important for cardiovascular health and preventing metabolic diseases. The nuclear receptors REV-ERB-α and REV-ERB-β have an integral role in regulating the expression of core clock proteins driving rhythms in activity and metabolism. Administration of synthetic REV-ERB ligands alters circadian behaviour and the circadian pattern of core clock gene expression in the hypothalami of mice. The circadian pattern of expression of an array of metabolic genes in the liver, skeletal muscle and adipose tissue was also altered, resulting in increased energy expenditure. Treatment of diet-induced obese mice with a REV-ERB agonist decreased obesity by reducing fat mass and markedly improving dyslipidaemia and hyperglycaemia. These results indicate that synthetic REV-ERB ligands that pharmacologically target the circadian rhythm may be beneficial in the treatment of sleep disorders as well as metabolic diseases.
| Targets |
REV-ERBα(IC50 = 790 nM); REV-ERBβ(IC50 = 560 nM)
|
|---|---|
| ln Vitro |
In HEK293 cells expressing chimeric Gal4 DNA-binding domain (DBD)-REV-ERB ligand-binding domain (LBD) α or β and a Gal4-responsive luciferase reporter gene (REV-), SR9011 dose-dependently boosts REV-ERB-dependent repressor activity. REV-ERBβ IC50 = 560 nM, ERBα IC50 = 790 nM. SR9011 potently suppressed transcription (SR9011 IC50=620 nM) in a co-transfection test using full-length REV-ERBα and a luciferase reporter driven by the Bmal1 promoter. SR9011 suppresses the expression of BMAL1 mRNA in HepG2 cells in a manner that is dependent on REV-ERBα/β [1]. In addition, SR9011 prevents the growth of breast cancer cell lines irrespective of their ER or HER2 status. It seems that SR9011 stops breast cancer cells' cell cycle before they reach the M phase. Since cyclin A (CCNA2) was found to be a direct target gene of REV-ERB, cell cycle arrest may be mediated by SR9011's suppression of this cyclin's expression. G0/G1 phase cells increased and S and G2/M phase cells decreased after treatment with SR9011, indicating that REV-ERB activation may reduce the transition from G1 to S phase and/or from S phase to G2/M phase [2].
|
| ln Vivo |
Since SR9011 demonstrated a respectable plasma exposure, the expression of genes sensitive to REV-ERB was investigated in the livers of mice given varying dosages of SR9011 for a period of six days. In response to SR9011, the REV-ERB target gene plasminogen activator inhibitor type 1 (Serpine1) shows dose-dependent expression inhibition. The genes for sterol response element binding protein (Srepf1) and cholesterol 7α-hydroxylase (Cyp7a1) were similarly demonstrated to be responsive to REV-ERB and to be dose-dependently inhibited by increasing dosages of SR9011. After 12 days in D:D circumstances, mice were injected at CT6 (peak expression of Rev-erbα) with a single dosage of SR9011 or vehicle. There is no disruption to circadian locomotor activity by vehicle injection. SR9011 treatment, however, resulted in the loss of locomotor activity in the subjects during the dark period. The following circadian cycle returns to normal, which is consistent with the drug clearing in a day. The efficacy (ED50 = 56 mg/kg) of the SR9011-dependent suppression of the REV-ERB responsive gene, Srebf1, in vivo (ED50 = 67 mg/kg) was comparable to that of the SR9011-dependent reduction in mouse wheel running behavior under continuous dark conditions[1].
|
| Enzyme Assay |
In this study, researchers developed two REV-ERBα/β agonists with sufficient plasma/brain exposure to allow evaluation of their effects in vivo. Both SR9009 and SR9009 (Fig. 1a, Supplementary Fig. 1) dose-dependently increased the REV-ERB-dependent repressor activity assessed in HEK293 cells expressing a chimeric Gal4 DNA Binding Domain (DBD) - REV-ERB ligand binding domain (LBD) α or β and a Gal4-responsive luciferase reporter (Fig. 1b) (SR9009: REV-ERBα IC50=670 nM, REV-ERBβ IC50=800 nM; SR9011: REV-ERBα IC50=790 nM, REV-ERBβ IC50=560 nM). The REV-ERB ligand GSK4112 (Supplementary Fig. 2), which exhibits no plasma exposure displays limited activity (Fig. 1b). Both SR9011 and SR9009 potently and efficaciously suppressed transcription in a cotransfection assay using full-length REV-ERBα along with a luciferase reporter driven by the Bmal1 promoter (Fig. 1c) (SR9009 IC50=710 nM; SR9011 IC50=620 nM). SR9011 and SR9009 suppressed the expression of BMAL1 mRNA in HepG2 cells in a REV-ERBα/β-dependent manner (Supplementary Fig. 3). Consistent with both compounds functioning as direct agonists of REV-ERB, we noted that the compounds increased the recruitment of the CoRNR box peptide fragment of NCoR using a biochemical assay (Supplementary Fig. 4). Direct binding of the SR9009 to REV-ERBα was also confirmed using circular dichrosim analysis (Supplementary Fig. 5) (Kd=800 nM). Neither compound exhibited activity at other nuclear receptors12,13 (Supplementary Fig. 6)[1].
|
| Cell Assay |
HEK293 cells are grown in 96-well plates (1×106/well) and are transiently transfected using Lipofectamine. Cells are transfected with a total of 200 ng of DNA per well consisting of the pGL4 mIL-17 firefly luciferase reporter construct, the pGL4 mIL-17 + CNS-5 firefly luciferase reporter construct, or the pGL4 mIL-17 2kB RORE mutant (100 ng/well) , an actin promoter Renilla reniformis luciferase reporter (50 ng/well), and either control vector alone or the test DNA (full-length RORα or full-length RORγ at 50 ng/well). All 48 human nuclear receptors are represented in the specificity assay and SR9009 is tested at a concentration of 20 μM. The format of the assay is a cotransfection assay with Gal4 DNA binding domain-nuclear receptor fusions in HEK293 cells[1].
|
| Animal Protocol |
For circadian gene expression experiments male C57BL6 mice (8–10 weeks of age) were either maintained on a L:D (12h:12h) cycle or on constant darkness. At circadian time (CT) 0 animals were administered a single dose of 100 mg/kg SR9009 or SR9011 (i.p.) and groups of animals (n=6) were sacrificed at CT0, CT6, CT12 and CT18. Gene expression was determined by real time QPCR.[1]
|
| References | |
| Additional Infomation |
SR-9011 is a REV-ERB agonist. SR-9011 has been demonstrated that it is specifically lethal to cancer cells and oncogene-induced senescent cells, including melanocytic naevi, and has no effect on the viability of normal cells or tissues.
Synchronizing rhythms of behaviour and metabolic processes is important for cardiovascular health and preventing metabolic diseases. The nuclear receptors REV-ERB-α and REV-ERB-β have an integral role in regulating the expression of core clock proteins driving rhythms in activity and metabolism. Here we describe the identification of potent synthetic REV-ERB agonists with in vivo activity. Administration of synthetic REV-ERB ligands alters circadian behaviour and the circadian pattern of core clock gene expression in the hypothalami of mice. The circadian pattern of expression of an array of metabolic genes in the liver, skeletal muscle and adipose tissue was also altered, resulting in increased energy expenditure. Treatment of diet-induced obese mice with a REV-ERB agonist decreased obesity by reducing fat mass and markedly improving dyslipidaemia and hyperglycaemia. These results indicate that synthetic REV-ERB ligands that pharmacologically target the circadian rhythm may be beneficial in the treatment of sleep disorders as well as metabolic diseases.[1] |
| Molecular Formula |
C23H31CLN4O3S
|
|
|---|---|---|
| Molecular Weight |
479.04
|
|
| Exact Mass |
478.18
|
|
| Elemental Analysis |
C, 57.67; H, 6.52; Cl, 7.40; N, 11.70; O, 10.02; S, 6.69
|
|
| CAS # |
1379686-29-9
|
|
| Related CAS # |
SR9011 hydrochloride;2070014-94-5
|
|
| PubChem CID |
57394021
|
|
| Appearance |
Light yellow to yellow solid powder
|
|
| Density |
1.3±0.1 g/cm3
|
|
| Boiling Point |
642.8±50.0 °C at 760 mmHg
|
|
| Flash Point |
342.6±30.1 °C
|
|
| Vapour Pressure |
0.0±1.9 mmHg at 25°C
|
|
| Index of Refraction |
1.595
|
|
| LogP |
5.74
|
|
| Hydrogen Bond Donor Count |
1
|
|
| Hydrogen Bond Acceptor Count |
5
|
|
| Rotatable Bond Count |
10
|
|
| Heavy Atom Count |
32
|
|
| Complexity |
600
|
|
| Defined Atom Stereocenter Count |
0
|
|
| InChi Key |
PPUYOYQTTWJTIU-UHFFFAOYSA-N
|
|
| InChi Code |
InChI=1S/C23H31ClN4O3S/c1-2-3-4-12-25-23(29)27-13-11-19(16-27)15-26(14-18-5-7-20(24)8-6-18)17-21-9-10-22(32-21)28(30)31/h5-10,19H,2-4,11-17H2,1H3,(H,25,29)
|
|
| Chemical Name |
|
|
| Synonyms |
|
|
| HS Tariff Code |
2934.99.9001
|
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
|
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
|
|||
|---|---|---|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.22 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.22 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0875 mL | 10.4375 mL | 20.8751 mL | |
| 5 mM | 0.4175 mL | 2.0875 mL | 4.1750 mL | |
| 10 mM | 0.2088 mL | 1.0438 mL | 2.0875 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
SR9011 and SR9009 are synthetic REV-ERB agonists with activityin vivo.Nature.2012 Mar 29;485(7396):62-8 |
Synthetic REV-ERB ligands alter circadian behavior and the pattern of expression of core clock genes.Nature.2012 Mar 29;485(7396):62-8. |
Activation of REV-ERB by SR9011in vivoresults in an increase in energy expenditure and weight loss.Nature.2012 Mar 29;485(7396):62-8. |
REV-ERB ligands alter the pattern of circadian expression of metabolic genes in the liver, skeletal muscle and adipose tissue.Nature.2012 Mar 29;485(7396):62-8. |
SR9009 treatment results in a decrease in fat mass and in plasma lipids in diet-induced obese mice.Nature.2012 Mar 29;485(7396):62-8. |
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA
