SR-9011 REV-ERB agonist


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Regulation of circadian behaviour
and metabolism by synthetic
REV-ERB agonists
Laura A. Solt1
*, Yongjun Wang1
*, Subhashis Banerjee1
, Travis Hughes1
, Douglas J. Kojetin1
, Thomas Lundasen1
, Youseung Shin2
Jin Liu1
, Michael D. Cameron2
, Romain Noel2
, Seung-Hee Yoo3
, Joseph S. Takahashi3
, Andrew A. Butler4
, Theodore M. Kamenecka2
& Thomas P. Burris1,5
Synchronizing rhythms of behaviour and metabolic processes is important for cardiovascular health and preventing
metabolic diseases. The nuclear receptors REV-ERB-a and REV-ERB-b 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.
In mammals, most if not all tissues display a self-sustaining circadian
molecular pacemaker that is responsible for aligning rhythms in various physiological functions. The suprachiasmatic nucleus (SCN) of
the hypothalamus functions as the master circadian pacemaker, synchronizing behavioural and physiological rhythms to the environmental
light/dark cycle1
. Optimal coordination of rhythms in metabolic processes with nutrient availability involves signals emanating from the
SCN and hypothalamus, as well as autonomous inputs from nutrient
sensors responding to metabolic flux and body temperature2
The mammalian molecular clock is composed of a transcriptional
feedback loop where heterodimers of the transcription factors BMAL1
(brain and muscle ARNT-like protein 1) and CLOCK (circadian locomotor output cycles kaput) or NPAS2 (neuronal PAS domaincontaining protein 2) activate the transcription of the period (Per1,
Per2 and Per3) and cryptochrome (Cry1 and Cry2) genes. Subsequently the PER and CRY proteins feedback to inhibit BMAL1–
CLOCK activity, resulting in a rhythmic, circadian pattern of expression
of these genes3
REV-ERB agonists modulate circadian behaviour
On the basis of the effects of these compounds on SCN clock activity,
we predicted that administration of these compounds would alter
circadian behaviour. Circadian locomotor activity was examined in
mice released into constant dark (D/D) conditions after 1 week of
housing in wheel cages in a standard light/dark (L/D) setting. After
12 days in D/D conditions mice were injected with a single dose of
SR9011, SR9009 or vehicle at circadian time 6 (CT6 (6 h after lights
on); peak expression of Rev-erb-a (Supplementary Fig. 9)). Vehicle
injection caused no disruption in circadian locomotor activity
(Fig. 2a, top panels). However, administration of a single dose of
either REV-ERB agonist resulted in loss of locomotor activity during
the subject dark phase (Fig. 2a, bottom panels). Normal activity
returned the next circadian cycle, consistent with clearance of the
drugs in less than 24 h. This effect was not due to toxicity as the
complete loss of locomotor activity was not observed in an identical
experiment using L/D conditions (Fig. 2d). Additionally, mice treated
with SR9011 did not display a decrease in strength (Supplementary
Fig. 10a) and continued to move as detected in an open field assay
(Supplementary Figs 10b, c). Furthermore, we observed no overt
toxicity when we examined complete blood counts (Supplementary
Fig. 11). We observed that the SR9011-dependent decrease in wheel
running behaviour in the mice under constant darkness conditions
was dose-dependent (Fig. 2b) and that the potency (half-maximum
effective dose (ED50) 5 56 mg kg21
) was similar to the potency of
SR9011-mediated suppression of a REV-ERB responsive gene,
Srebf1, in vivo (ED50 5 67 mg kg21
). Tau was not affected by treatment with either drug (data not shown), and the recovery after the
drug to resume the normal rhythm is similar to the effect observed
after removal of the drug from the SCN explants (Fig. 1d).
We next assessed the expression of core clock genes in hypothalami
isolated from mice in D/D conditions. Mice were injected with a single
dose of SR9011 or SR9009 at CT0 and hypothalami collected for
expression analysis. We observed a range of effects on the pattern
of expression of the core clock genes. The amplitude of Per2 expression was enhanced whereas Cry2 was suppressed (Fig. 2c). Bmal1
expression was affected more


The circadian clock protects against acute radiation-induced dermatitis 

Panshak P Dakup, Kenneth I Porter, Shobhan Gaddameedhi 

Toxicology and Applied Pharmacology, 115040, 2020 



The circadian clock protects against ionizing radiationinduced cardiotoxicity 

Panshak P Dakup, Kenneth I Porter, Rajendra P GajulaPeeyush N GoelZhaokang Cheng, Shobhan Gaddameedhi 

The FASEB Journal, 2020 


In pancreatic islets from type 2 diabetes patients, the dampened circadian oscillators lead to reduced insulin and glucagon exocytosis 

Volodymyr Petrenko, Nikhil R Gandasi, Daniel Sage, Anders Tengholm, Sebastian BargCharna Dibner 

Proceedings of the National Academy of Sciences 117 (5), 2484-2495, 2020 

Circadian clocks operative in pancreatic islets participate in the regulation of insulin secretion in humans and, if compromised, in the development of type 2 diabetes (T2D) in rodents. Here we demonstrate that human islet α- and β-cells that bear attenuated clocks exhibit strongly disrupted insulin and glucagon granule docking and exocytosis. To examine whether compromised clocks play a role in the pathogenesis of T2D in humans, we quantified parameters of molecular clocks operative in human T2D islets at population, single islet, and single islet cell levels. Strikingly, our experiments reveal that islets from T2D patients contain clocks with diminished circadian amplitudes and reduced in vitro synchronization capacity compared to their nondiabetic counterparts. Moreover, our data suggest that islet clocks orchestrate temporal profiles of insulin and glucagon secretion in a physiological context. This regulation was disrupted in T2D subjects, implying a role for the islet cell-autonomous clocks in T2D progression. Finally, Nobiletin, an agonist of the core-clock proteins RORα/γ, boosted both circadian amplitude of T2D islet clocks and insulin secretion by these islets. Our study emphasizes a link between the circadian clockwork and T2D and proposes that clock modulators hold promise as putative therapeutic agents for this frequent disorder. 

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Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis 

Qingya Shi, Fen Pei, Gary A Silverman, Stephen C Pak, David H Perlmutter, Bing Liu, Ivet Bahar 

International journal of molecular sciences 21 (8), 2855, 2020 



Disrupting the key circadian regulator CLOCK leads to age-dependent cardiovascular disease 

FJ Alibhai, J LaMarre, CJ Reitz… - Journal of molecular and …, 2017 – Elsevier 

… Furthermore, SR9009 attenuates cardiac hypertrophy in mice subjected to transverse aortic constriction (TAC), supporting that the circadian mechanism plays an … Pharmacological targeting of the circadian mechanism provides a new opportunity for treating heartdisease 


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