SR9011 vs SR9009, which is better?

Physiological processes involving metabolism and behavior, e.g., activity/rest, are generally organized on a cycle of approximately 24 h driven by a circadian rhythm. The nuclear receptors reversed-viral erythroblastosis α and β (REV-ERB α and β) regulate the expression of core clock proteins and therefore help to modulate the circadian rhythm. SR-9009 and SR-9011 both work through these pathways, but it is not evident in the literature which is more powerful.

Modulation of the REV-ERB activity by synthetic agonists, e.g., SR9009 and SR9011 (Figure 1), alters the expression of genes involved in lipid and glucose metabolism and, therefore, plays an important role in maintaining the energy homeostasis. Effects of SR9009 and SR9011 observed via in vitro and in vivo animal studies were increased basal oxygen consumption, decreased lipogenesis, cholesterol and bile acid synthesis in the liver, increased mitochondrial content, glucose and fatty acid oxidation in the skeletal muscle and decreased lipid storage in the white adipose tissue.

SR9011 was slightly different in that it reduced neuorinflammatory markers. It has a positive role to play in immunometabolic processes. It disturbed rhythmic expression of clock genes in microglia. Pro-inflammatory cytokine expression was attenuated by SR9011 during an immune challenge by TNFα, while expression of the anti-inflammatory cytokine Il10 was stimulated. However, SR9011 decreased phagocytic activity, mitochondrial respiration, ATP production, and metabolic gene expression.

On the other hand, SR9011 has demonstrated potential in arresting the development of breast cancers. REV-ERBα and REV-ERBβ are nuclear receptors that are ligand-dependent transcriptional repressors. Heme is the natural ligand for these receptors, but several synthetic agonists and antagonists have been designed recently. The gene that encodes REV-ERBα, NR1D1, is closely associated with ERBB2, the gene that encodes the HER2 oncogene, which is amplified in HER2+ breast cancers. We examined the effect of a synthetic REV-ERB agonist, SR9011, on a range of estrogen receptor positive (ER+), ER−, HER2+, HER2− and triple negative breast cancer cell lines. We found that SR9011 suppressed proliferation of the breast cancer cell lines regardless of their ER or HER2 status. SR9011 had no effect on MCF10A cell proliferation. SR9011 appears to pause the cell cycle of the breast cancer cells prior to M phase. Cyclin A (CCNA2) was identified as a direct target gene of REV-ERB suggesting that suppression of expression of this cyclin by SR9011 may mediate the cell cycle arrest. These data indicate that synthetic REV-ERB ligands may hold utility in treatment of diseases associated with uncontrolled cellular proliferation such as cancer.

SR9009 has demonstrated capability in dealing with aggressive brain tumours, lung cancers and even prostate cancer. The REV-ERB agonist SR9009 is specifically lethal to both chemosensitive and chemoresistant small-cell lung cancer (SCLC) cells. REV-ERBα was involved in the antitumor effect of SR9009 in SCLC. The core autophagy gene Atg5 was identified as a direct downstream target of REV-ERBα and was suppressed by the REV-ERB agonist SR9009 in SCLC. Furthermore, the interaction of REV-ERBα with this autophagy gene impaired autophagy activity, leading to SR9009 cytotoxicity in SCLC cells.

The study provided a novel viewpoint indicating that the REV-ERB agonist SR9009 could be a novel and promising therapeutic strategy in first- or second-line SCLC treatment.

Glioblastoma multiforme is the most aggressive brain tumor, and human T98G cells constitute a useful glioblastoma multiforme model to evaluate the chemotherapeutic agents. Modern life (shiftwork, jetlag, etc.) may cause circadian disorganization promoting higher cancer risk and metabolic disorders. Pharmacological modulation of circadian components may offer selective anticancer strategies. REV-ERBs are heme-binding circadian clock components acting as repressors of processes involved in tumorigenesis such as metabolism, proliferation, and inflammation. A synthetic pyrrole derivative (SR9009) that acts as REV-ERBs-specific agonists exhibits potent in vivo activity on metabolism and tumor cell viability. SR9009's effects on T98G cell viability was investigated; differential chemotherapy time responses, and underlying metabolic processes (reactive oxygen species [ROS] and lipid droplets [LDs]) all compared with the proteasome inhibitor Bortezomib treatment. SR9009-treated cells exhibited significant reduction in cell viability with consequences on cell cycle progression. Results suggest that the pharmacological modulation of the tumor-intrinsic clock by REV-ERB agonists severely affects cell metabolism and promotes cytotoxic effects on cancer cells.

SR-9009 has been tested on prostate cancer in a recent study published in Nature, it was found that SR9009 was specifically lethal to PCa cell lines but had no cytotoxic effect on prostate cells. SR9009 significantly inhibited colony formation, the cell cycle, and cell migration and promoted apoptosis in PCa cells. SR9009 treatment markedly inhibited prostate cancer subtype 1 (PCS1), the most lethal and aggressive PCa subtype, through FOXM1 pathway blockade, while it had no impacts on PCS2 and PCS3.

While both products are cardioprotective and good for heart health, another indication that SR9011 was tested for is pulmonary arterial hypertension (PAH). It has been noted that common to all patients is a measure of metabolic dysfunction. Metabolic dysfunction is increasingly being tied to dysregulated circadian rhythms. Inhibited activity at nuclear receptor REV-ERBa has been demonstrated to coincide with the onset of PAH, ergo it was theorised that SR9011 may well be a useful intervention. When tested on rats this normalised hemodynamics, increased apoptosis and reversed vascular remodelling.

In sum, it appears that the two compounds differ slightly in terms of which specific health concerns they are best suited to remediating. It is not clear however which has identifiably greater potential in fat oxidation or metabolic upregulation. Nor is it clear whether there is any difference in rate of excretion and length of half-life.

The Effect of Rev-erbα Agonist SR9011 on the Immune Response and Cell Metabolism of Microglia, Front. Immunol., 25 September 2020 Sec. Inflammation, Volume 11 - 2020

Yongjun Wanga, Douglas Kojetinb, Thomas P.Burrisa, Anti-proliferative actions of a synthetic REV-ERBα/β agonist in breast cancer cells, Anti-proliferative actions of a synthetic REV-ERBα/β agonist in breast cancer cells, Biochemical Pharmacology

Volume 96, Issue 4, 15 August 2015, Pages 315-322

Therapeutic Potential of the Nuclear Receptor Modulator SR9011 for Treatment of Pulmonary Hypertension R. Paulin, M.-C. Lampron, G. Vitry, Y. Grobs, O. Boucherat, S. Provencher, S. Bonnet,

Weitao Shen, Wei Zhang, Weilin Ye, Haihong Wang, Qingxi Zhang, Jie Shen, Qingsha Hong, Xiang Li,5 Ge Wen, Ting Wei, and Jian Zhang, SR9009 induces a REV-ERB dependent anti-small-cell lung cancer effect through inhibition of autophagy Theranostics. 2020; 10(10): 4466–4480. Published online 2020 Mar 15. doi: 10.7150/thno.42478 PMCID: PMC7150483 PMID: 32292508

Paula M. Wagner, Natalia M. Monjes, and Mario E. Guido, Chemotherapeutic Effect of SR9009, a REV-ERB Agonist, on the Human Glioblastoma T98G Cells, American Society for Neurochemistry, Volume 11: 1–14