SR9011

Founding pharmacology, Scripps Research Institute, 2012

The paper that introduced SR9011 and SR9009 reported receptor activity in HEK293 reporter assays (SR9011 half-maximal inhibitory concentration 790 nanomolar at REV-ERB-alpha and 560 nanomolar at REV-ERB-beta), suppression of a Bmal1 promoter reporter, increased corepressor recruitment, reversible suppression of oscillation amplitude in suprachiasmatic nucleus explants, dose-dependent suppression of REV-ERB target genes in mouse liver, loss of a full active period after a single 100 mg/kg intraperitoneal dose in constant darkness, a 1 to 3 hour delay in activity onset under a light and dark cycle, and, over 10 days of twice-daily dosing, about 5 percent higher oxygen consumption, about 15 percent less movement, unchanged food intake and lower fat mass. The matching experiments in diet-induced obese mice (for example a 47 percent fall in plasma cholesterol and a 19 percent fall in plasma glucose) were done with SR9009 rather than SR9011 (PMID: 22460951).

Sleep and behaviour, Scripps Research Institute, 2014

In mice implanted for electroencephalography, SR9011 at 100 mg/kg intraperitoneally in the middle of the rest period raised wakefulness for about 2 hours, fragmented slow-wave sleep into more and shorter episodes, almost abolished REM sleep for 3 hours and kept core temperature about 0.5 degrees Celsius above that of vehicle-treated mice for about 2 hours (less than the rise typical of wakefulness in the dark), with a sleep recovery period after lights out; the same dose in the active period had no effect on sleep. Chronic twice-daily dosing reduced anxiety-like behaviour in six separate assays with a half-maximal effective dose of 61 mg/kg, comparable to a benzodiazepine comparator, and the effect was absent in REV-ERB-beta-null mice (PMID: 25536025). A later study used SR9009 in REV-ERB-beta-deficient mice and confirmed that the receptor is needed for the wake-inducing effect (PMID: 29355503).

Cancer cell and mouse tumour studies

A 2018 Nature paper from the Salk Institute reported that SR9009 and SR9011 were lethal to cancer cell lines from brain, leukemia, breast, colon and melanoma and to oncogene-induced senescent cells such as melanocytic naevi, without affecting the viability of normal cells or tissues; the mechanism was inhibition of autophagy and de novo lipogenesis, apoptosis did not require p53 and persisted under low oxygen, and knocking down REV-ERB-alpha and REV-ERB-beta removed the effect. The in vivo glioblastoma work in that paper used SR9009 (PMID: 29320480). An earlier study found SR9011 suppressed proliferation of estrogen receptor positive and negative and HER2 positive and negative breast cancer cell lines while leaving MCF10A cells alone, and identified cyclin A as a direct REV-ERB target (PMID: 26074263). In osteosarcoma, SR9011 was one of four nuclear receptor modulators that inhibited proliferation of U2OS, HOS-MNNG and Saos-2 cells without inhibiting normal osteoblasts, reduced tumour growth in mice and lost its effect in receptor-knockout cells (PMID: 36681687).

Inflammation, fibrosis and organ models

• SR9011 suppressed lipopolysaccharide-induced microglial activation through the NF-kB pathway in BV2 cells, in primary mouse microglia and after microinjection into the mouse ventral midbrain (PMID: 29950615). In primary rat microglia, SR9011 disturbed clock gene rhythms, lowered pro-inflammatory cytokine expression during a TNF-alpha challenge, and lowered phagocytosis, mitochondrial respiration and ATP production (PMID: 33101272).
• In WI-38 human lung fibroblasts, SR9011 and two other Rev-erb-alpha agonists reduced the fibroblast-to-myofibroblast transition, collagen I secretion, interleukin 6 release and alpha smooth muscle actin expression driven by TGF-beta 1 (PMID: 37269594).
• The Rev-erb-alpha ligand SR9011 eased disease severity in a mouse model of asthma by suppressing T helper 2 responses, in work that identified GATA3 as a direct Nr1d1 target (PMID: 35596832).
• SR9011 suppressed hypoxia-induced erythropoietin expression in mice, consistent with Rev-erb-alpha acting as a negative regulator of the Epo gene (PMID: 38748870).
• SR9011 reduced disease severity in MPTP-treated mice, a Parkinson's disease model, and reduced MPP-induced toxicity in SH-SY5Y cells in a study of Rev-erb-alpha and Sox2 (PMID: 39084577).
• A hydrogel carrying SR9011 for sustained intestinal release reduced inflammation, lowered CD47 and preserved epithelial integrity in mice with dextran sulfate sodium colitis; the authors note that pharmacokinetic analysis was limited to colonic tissue (PMID: 41163542).
• In a dry eye study, SR9011 restored lacrimal gland function in mice after corneal injury and reversed impaired lipid metabolism attributed to lower Nr1d2 (PMID: 40885436).
• In female mice with disrupted circadian rhythm, SR9011 raised the fertility index and improved measures of follicle development (PMID: 41788764).
• SR9011 is also used as a tool to abolish circadian rhythms in cells, for example in the circadian rhythm of primary cilium length in fibroblasts (PMID: 37971148) and in the clock-dependent regulation of interleukin 6 in microglia (PMID: 27726182).

Most of these are single studies, several come from the same group in Chandigarh, and none involved a human participant.

Doping control literature

SR9011 appears in anti-doping work rather than clinical work. A 2016 Ghent University study identified 14 phase I metabolites of SR9011 and 8 of SR9009 in human liver microsomes, demonstrated SR9009 in a product bought over the internet, and found neither compound nor their metabolites in a retrospective search of 1,511 doping control samples (PMID: 27706103). A review of emerging drugs affecting skeletal muscle and mitochondrial biogenesis listed SR9009 and SR9011 among the compounds anti-doping laboratories were preparing for (PMID: 26842585), and a quantitative method for both compounds in horse plasma was validated and applied to thoroughbreds given SR9009 (PMID: 35396832).

Target specificity

Work in a conditional double-knockout mouse model showed that SR9009 altered cell viability, metabolism and transcription in cells lacking both REV-ERB-alpha and REV-ERB-beta, so its effects cannot stand in for REV-ERB activity (PMID: 31127047). That test has been published for SR9009 and not for SR9011. The receptor-dependence results for SR9011 come from knockdown or knockout in cancer cell lines (PMID: 29320480, PMID: 36681687) and from the absence of its anxiolytic and wake-promoting effects in REV-ERB-beta-null mice (PMID: 25536025).

What the mouse studies recorded

The single most striking finding in the founding paper is the complete loss of locomotor activity during the subjective night after one injection of 100 mg/kg in constant darkness. The Scripps authors argued this was clock disruption rather than poisoning, because it did not happen in mice kept on a normal light and dark cycle, grip strength did not fall, the mice still moved in an open field, and complete blood counts showed no overt toxicity (PMID: 22460951). Over 10 days of twice-daily dosing, movement fell about 15 percent (PMID: 22460951). In the sleep study, REM sleep was almost abolished for 3 hours after a single injection, and the mice then slept more after the lights went out (PMID: 25536025).

Cell findings that read as warnings

In primary rat microglia, SR9011 disturbed the rhythmic expression of clock genes, lowered pro-inflammatory cytokine expression during a challenge with TNF-alpha, and also reduced phagocytic activity, mitochondrial respiration, ATP production and metabolic gene expression (PMID: 33101272). Cancer biology treats the cytotoxicity as the intended effect: SR9009 and SR9011 killed cancer cell lines and oncogene-induced senescent cells by blocking autophagy and fat synthesis, and the same report found no effect on the viability of normal proliferating or quiescent cells or on normal mouse skin and brain tissue (PMID: 29320480). A compound that stops autophagy and de novo lipogenesis in dividing cells has no established margin in healthy people.

The off-target question

For the sister compound SR9009, effects on cell viability, metabolism and transcription persisted in cells with both REV-ERB proteins deleted, which means at least part of what that compound does has nothing to do with the intended target (PMID: 31127047). No equivalent test of SR9011 was found, so the share of its effects that are REV-ERB-dependent is unmeasured in whole animals.

Products and testing

In vitro metabolism work on human liver microsomes identified 14 phase I metabolites of SR9011 and 8 of SR9009, and the authors were able to demonstrate SR9009 in a product bought over the internet; a retrospective search of 1,511 doping control samples previously run on a full-scan screening method found neither parent compound nor their metabolites (PMID: 27706103). A 2017 analysis of 44 products sold online as selective androgen receptor modulators found that 17 contained a different unapproved drug, with SR9009 named among them; SR9011 was not among the compounds reported in that analysis (PMID: 29183075).

Gaps

No human pharmacokinetic, long-term, reproductive or drug interaction data exist for SR9011. No study has established an oral dose in any species in the papers retrieved for this guide, and the mouse results above came from injected doses.