SR9009

Description

SR-9009 is an agonist at nuclear receptor Rev-ErbA. Greatly diminishes VILI-induced lung edema, inflammatory cell infiltration and TNFα production in a rat lung injury model. SR-9009 suppresses atherosclerosis in a mouse model. Specifically lethal to cancer cells and oncogene-induced senescent cells with no effect on the viability of normal cells or tissues. Disrupts pain associated with osteoarthritis by reducing BMAL1 expression in bmal1f/fNav1.8CreERT mice.

Uses

SR 9009 is a synthetic REV-ERB agonist that regulates circadian behavior and metabolism; has potential use in the treatment of sleep disorders and metabolic diseases. It is a lead compound for a new class of cancer drugs associated with the body’s circadian clock.

Pharmaceutical Applications

SR9009 is a research drug that was developed by professor Thomas Burris of the Scripps Research Institute as an agonist of Rev-ErbA (i.e., increases the constitutive repression of genes regulated by Rev-ErbA) with a half-maximum inhibitory concentration (IC50) = 670 nM for Rev-ErbAα and IC50 = 800 nM for Rev-ErbAβ.

Biological Activity

REV-ERBα and REV-ERBβ nuclear receptors are transcriptional repressors that coordinate circadian rhythm and metabolic pathways in a heme-dependent manner. SR9009 is a REV-ERB agonist that increases the constitutive repression of genes regulated by REV-ERBα and REV-ERBβ with IC50 values of 670 and 800 nM, respectively. Through activation of REV-ERB, SR9009 has been shown to decrease circadian locomotor activity during the dark phase and to alter the expression pattern of core clock genes 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 shown to be altered in mice exposed to SR9009, resulting in increased energy expenditure. Diet-induced obese mice treated with 100 mg/kg SR9009 (i.p. two times a day for 30 days) have been reported to display decreased fat mass and markedly improved dyslipidemia and hyperglycemia.

Side effects

So far, no side effect caused by SR9009 has been identified. It can then be rightly said that the supplement is very safe to consume. SR9009 does not influence the hormones in any way and so won’t aromatize into the estrogen, and won't suppress the production of testosterone. Just like other supplements like SARMS, SR9009 does not deposit toxins in the liver, though it is needful for there to be some supplements that will support the liver when using it. 3 to 5 capsules of N2Guard taken every day will serve as good support to the kidney and liver.

in vitro

IC50: 670 nM for REV-ERB-α and 800 nM for REV-ERB-β
SR9009, also known as Stenabolic, is a research drug as agonist of REV-ERB.
REV-ERB-α and REV-ERB-β, two nuclear receptors, have a critical role in regulating the expression of core clock proteins driving rhythms in activity and metabolism.
In vitro: Both SR9009 and its analog SR9011 could dose-dependently increase the REV-ERB-dependent repressor activity assessed in HEK293 cells expressing a chimaeric Gal4 DNA binding domain: REV-ERB ligand binding domain α or β and a Gal4-responsive luciferase reporter. In addition, SR9009 was found to be able to suppress BMAL1 messenger RNA expression in HepG2 cells in a REV-ERB-α/β-dependent manner.
In vivo: Mice were treated with a single dose of SR9009, SR9011 or vehicle at circadian time 6 (CT6 (6h after lights on) after 12 days in D/D conditions showing peak expression of Rev-erb-α. Results showed that vehicle injection caused no disruption in circadian locomotor activity. In contrast, administration of a single dose of either SR9009 or SR9011 led to the loss of locomotor activity during the subject dark phase. In addition, the normal activity returned the next circadian cycle, which was consistent with clearance of the drugs in less than 24h.
Clinical trial: Up to now, SR9009 is still in the preclinical development stage.

storage

Store at +4°C

References

1) Solt et al. (2012) Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists; Nature, 485 62
2) Li et al. (2014) A study on circadian rhythm disorder of rat lung tissue caused by mechanical ventilation induced lung injury; Int.Immunopharmacol. 18 249
3) Sitaula et al. (2015) Suppression of atherosclerosis by synthetic REV-ERB agonist; Biochem. Biophys. Res. Commun.,460 566
4) Sulli et al. (2018) Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence; Nature, 553 351
5) Das et al. (2018) Pharmacological targeting of the mammalian clock reveals a novel analgesic for osteoarthritis-induced pain; Gene 655 1
6) Solt LA,Wang Y,Banerjee S,Hughes T,Kojetin DJ,Lundasen T,Shin Y,Liu J,Cameron MD,Noel R,Yoo SH,Takahashi JS,Butler AA,Kamenecka TM,Burris TP. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature.2012 Mar 29;485(7396):62-8.