Description

SR9009

Capsules: 15mg/cap – 60 capsules

Application: Agonist of Rev-ErbA

Concentration: 1% (10mg/ml)

CAS: 1379686-30-2

Molar Mass: 437.94 g/mol

Chemical Formula: C20H24ClN3O4S

Synonyms: Stenabolic

Storage Minimize open air exposure, store in a cool dry place.

Peer-Reviewed Studies

SR9009 improves heart function after pressure overload independent of cardiac REV-ERB

Abstract
The core clock component REV-ERB is essential for heart function. Previous studies show that REV-ERB agonist SR9009 ameliorates heart remodeling in the pressure overload model with transverse aortic constriction (TAC). However, it is unknown whether SR9009 indeed works through cardiac REV-ERB, given that SR9009 might target other proteins and that REV-ERB in non-cardiac tissues might regulate cardiac functions indirectly. To address this question, we generated the REV-ERBα/β cardiac-specific double knockout mice (cDKO). We found that REV-ERB cardiac deficiency leads to profound dilated cardiac myopathy after TAC compared to wild-type (WT) control mice, confirming the critical role of REV-ERB in protecting against pressure overload. Interestingly, the cardioprotective effect of SR9009 against TAC retains in cDKO mice. In addition, SR9009 administered at the time points corresponding to the peak or trough of REV-ERB expression showed similar cardioprotective effects, suggesting the REV-ERB-independent mechanisms in SR9009-mediated post-TAC cardioprotection. These findings highlight that genetic deletion of REV-ERB in cardiomyocytes accelerates adverse cardiac remodeling in response to pressure overload and demonstrated the REV-ERB-independent cardioprotective effect of SR9009 upon pressure overload.

SR9009 Regulates Acute Lung Injury in Mice Induced by Sepsis

Abstract
Rev-Erbα is a nuclear heme receptor, transcriptional repressor, and critical component of the molecular clock that drives daily rhythms of metabolism. However, the roles of Rev-Erbα in acute lung injury (ALI) remain unclarified. Hence, the effect of Rev-Erbα on lung injury of sepsis mice is investigated here. The mice sepsis model is established using lipopolysaccharide (LPS) injection, and the expression levels of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) in both RAW246.7 cells and lung tissues, are tested. The inflammatory response is obviously enhanced in LPS-constructed sepsis mice and alleviated by SR9009 agonist treatment. Cell-based experiments reveal that pharmacological activation of Rev-Erbα via SR9009 attenuates the LPS-induced inflammatory response by suppressing TLR4-regulated NF-κB activation. Sepsis induces the increase in W/D ratio; promotes the levels of malondialdehyde (MDA), lactic acid (LA), and superoxide dismutase (SOD); and inhibits the levels of glutathione (GSH), whereas SR9009 treatment could effectively yield beneficial effects on metabolism. In addition, SR9009 treatment ameliorates acidosis and hypoxemia by efficiently decreasing arterial PaCO₂ and increasing arterial PaO₂, SO₂, HCO₃ ^–, lactic acid concentration, and blood PH. These findings confirm that SR9009 treatment can alleviate the sepsis-induced lung injury and targeting Rev-Erbα may represent a promising approach for the prevention and management of ALI.

Identification of a small molecule SR9009 that activates NRF2 to counteract cellular senescence

Abstract
The senescence-associated secretory phenotype (SASP) is a striking characteristic of senescence. Accumulation of SASP factors causes a pro-inflammatory response linked to chronic disease. Suppressing senescence and SASP represents a strategy to prevent or control senescence-associated diseases. Here, we identified a small molecule SR9009 as a potent SASP suppressor in therapy-induced senescence (TIS) and oncogene-induced senescence (OIS). The mechanism studies revealed that SR9009 inhibits the SASP and full DNA damage response (DDR) activation through the activation of the NRF2 pathway, thereby decreasing the ROS level by regulating the expression of antioxidant enzymes. We further identified that SR9009 effectively prevents cellular senescence and suppresses the SASP in the livers of both radiation-induced and oncogene-induced senescence mouse models, leading to alleviation of immune cell infiltration. Taken together, our findings suggested that SR9009 prevents cellular senescence via the NRF2 pathway in vitro and in vivo, and activation of NRF2 may be a novel therapeutic strategy for preventing cellular senescence.

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