Recent advances in modulators of circadian rhythms: an update and perspective

Figures & data

Figure 1. The physiological basis for the generation and maintenance of mammalian circadian rhythm. Reproduced from Chen et al.¹⁹

Figure 2. Molecular clock loops and their potential targets with representative small molecule modulators. CLOCK: circadian locomotor output cycles kaput; BMAL1: brain and muscle ARNT-like 1; CRY: cryptochrome; PER: period; ROR: RAR-related orphan receptor; RRE: retinoic acid receptor-related orphan receptor binding element; CCGs: clock-controlled genes; CK1: casein kinase 1; CDKs: cyclin-dependent kinases; GSK3β: glycogen synthase kinase 3β; SIRT1: silent information regulator 1; PPARγ: peroxisome proliferator-activated receptor γ; DNA TOPs: DNA topoisomerases. Reproduced from He and Chen⁴⁹. Copyright 2016 American Chemical Society.

Figure 3. The structure of modulators targeting CRYs.

Table 1. Modulators targeting CRYs.

Name	Activity	Actions	Physiological effects	Reference
KL001 (Compound 1)	IC50 = 14μM/0.82μM (measured by Bmal1-dLuc and Per2-dLuc reporter U2OS cells, Agonist)	Stabilise CRY, lengthen period, reduce amplitude	Inhibit glucagon-induced gluconeogenesis in primary hepatocytes	Hirota et al.^52, Nangle et al.^53
KL002 (Compound 2)	IC50 = 5.9μM/1.2μM (measured by Bmal1-dLuc and Per2-dLuc reporter U2OS cells, Agonist)	Stabilise CRY, lengthen period, reduce amplitude	Inhibit glucagon-induced gluconeogenesis in primary hepatocytes	Hirota et al.^52
KL003 (Compound 3)	IC50 = 4.4μM/0.66μM (measured by Bmal1-dLuc and Per2-dLuc reporter U2OS cells, Agonist)	Stabilise CRY, lengthen period, reduce amplitude	Inhibit glucagon-induced gluconeogenesis in primary hepatocytes	Hirota et al.^52
FAD (Compound 4)	/	Stabilise CRY proteins by competing with FBXL3, lengthen the circadian period	Light-independent mechanisms of FAD regulate CRY	Hirano et al.^54
KL044 (Compound 5)	log(EC50[M]) = –7.32 (Agonist)	Lengthen the circadian period, repress Per2 activity, and stabilise CRY	Inhibit glucagon-induced gluconeogenesis	Lee et al.^55
GO044 (Compound 6)	/ (Inhibitor)	Shorten period	/	Oshima et al.^56
GO200 (Compound 7)	/ (Inhibitor)			Oshima et al.^56
GO211 (Compound 8)	/ (Inhibitor)			Oshima et al.^56
KS15 (Compound 9)	EC50=0.49μM (Inhibitor)	Attenuate circadian oscillation, inhibit the repressive function of CRY1/2	Enhance E-box-mediated transcription	Chun et al.^57
50 (Compound 10)	EC50 = 0.363μM (measured by Per2-dLuc reporter U2OS cells, Agonist)	Lengthen the circadian period, repress Per2 activity, and stabilise CRY	Inhibit glucagon-induced gluconeogenesis	Humphries et al.^58
KL101 (Compound 11)	log[EC2h] = –5.79 (measured by Bmal1-dLuc cells, Agonist)	Stabilise CRY1 and lengthen period	Enhance brown adipocyte differentiation	Miller et al.^59
TH301 (Compound 12)	log[EC2h] = –6.03 (measured by Bmal1-dLuc cells, Agonist)	Stabilise CRY1/2 and lengthen period	Enhance brown adipocyte differentiation	Miller et al.^59

Figure 4. Development and structure of modulators targeting REV-ERBs.

Table 2. Modulators targeting REV-ERBs.

Name	Activity	Actions	Physiological effects	Reference
Heme (Compound 13)	IC50 = 0.05μM (measured by FRET assay, agonist)	Represses activity of REV-ERBα LBD	Regulates interaction between REV-ERBα and NCoR-HDAC3	Raghuram et al.^60, Yin et al.^61
GSK4112/SR6452 (Compound 14)	EC50 = 0.25μM (measured by FRET assay, agonist)	Resets the circadian oscillation of REV-ERB target genes, suppresses expression of REV-ERB target genes in cells	Inhibits expression of the circadian target gene bmal1	Meng et al.^64, Kumar et al.^65 Grant et al.^66
SR9009 (Compound 15)	IC50 = 0.67/0.80μM (measured by Gal4 reporter assay for REV-ERBα and REV-ERBβ, agonist) Kd = 0.8μM (measured by circular dichroism binding assay for REV-ERBα)	Amplitude reduction, suppresses RRE-mediated transcription	Improves glucose homeostasis in obese mice, promotes wakefulness, reduces anxiety	Solt et al.^67
SR9011 (Compound 16)	IC50 = 0.79/0.56μM (measured by Gal4 reporter assay for REV-ERBα and REV-ERBβ, agonist)	Amplitude reduction, suppresses RRE-mediated transcription	Improves glucose homeostasis in obese mice, promotes wakefulness, reduces anxiety	Solt et al.^67
GSK2945 (Compound 17)	EC50 = 0.05μM (measured by NCOR peptide recruitment for REV-ERBα, agonist)	Suppression and shift of the BMAL oscillation curve	Inhibits IL-6 production from human THP-1 cells	Trump et al.^68
12e (Compound 18)	EC50 = 0.7μM (measured by full-length Bmal1 reporter assay for REV-ERBα, agonist)	Suppresses expression of REV-ERB target genes in cells	Inhibits expression of the circadian target gene bmal1	Shin et al.^69
6j (Compound 19)	EC50 = 0.077μM (measured by full-length Bmal1 reporter assay for REV-ERBα, agonist)	Suppresses expression of REV-ERB target genes in cells	Inhibits expression of the circadian target gene bmal1	Noel et al.^70
KK-S6 (Compound 20)	IC50 = 3.95μM (measured by cell-based assay using the wtBmal1: Luc-transfected NIH3T3 cells, agonist)	Alters the amplitude of circadian oscillations of Bmal1 and Per2	Represses RORE-dependent transcriptional activity of mBmal1 promoter and reduces endogenous BMAL1 protein expression	Lee et al.^71
SR8278 (Compound 21)	IC50 = 0.47μM (measured using full-length Bmal1 reporter assay for REV-ERBα, Antagonist)	Increases expression of REV-ERB target genes in cells	Reduces glucagon secretion from mouse alpha cells	Kojetin et al.^72
ARN5187 (Compound 22)	IC50 = 17.5μM (measured using luciferase-based reporter assay, dual autophagy/REV-ERB inhibitor)	Direct interaction with the LBD of REV-ERBβ	Enhances the expression of BMAL1, PER1, and PEPCK, and blocks autophagy by disrupting the lysosomal function and preventing autophagolysosome final maturation	De Mei et al.^73
30 (Compound 23)	IC50 = 1.34μM (measured using luciferase-based reporter assay, dual autophagy/REV-ERB inhibitor)	Direct interaction with the LBD of REV-ERBβ	Enhances the expression of BMAL1, PER1, and PEPCK, and blocks autophagy by disrupting the lysosomal function and preventing autophagolysosome final maturation	Torrente et al.^74
GSK1362 (Compound 24)	inverse agonist	Protects REV-ERBα protein from degradation	Increases transcription of Bmal1	Pariollaud et al.^75
Chelidamic acid (Compound 25)	EC50 = 0.36μM (measured using mammalian cell-based two-hybrid system, agonist)	Binds specifically to the LBD site of REV-ERBα receptor	/	Hering et al.^76

Figure 5. Natural structure of modulators targeting RORs.

Figure 6. Development and structure of synthetic modulators targeting RORs.

Table 3 Representative modulators targeting RORs.

Name	Activity	Actions	Physiological effects	Reference
T0901317 (Compound 45)	Kd = 132 nM and 51 nM for RORα and RORγ (measured by radioligand displacement, inverse agonist)	Inhibits transactivation activity of RORα and RORγ but not RORβ	Suppresses G6PC and IL17 promoter activity	Kumar et al.^103
SR1078 (Compound 46)	IC50 = 2–5 μM for RORα and RORγ (measured by DualGloTM luciferase assay, agonist)	Decreases interaction between RORγ and the peptide fragment of TRAP220 co-activator	Increases the expression of RORα and RORγ target genes in vitro and in vivo	Wang et al.^105
SR1001 (Compound 47)	Ki = 172 and 111 nM for RORα and RORγ (measured by radioligand binding assay, inverse agonist)	Inhibits RORγ activity on the IL17 promoter	Inhibits expression of IL17A, IL17F, IL21, and IL22 in cells	Solt et al.^106
SR3335 (ML176, Compound 48)	Ki = 220 nM (measured by radioligand binding assay, partial inverse agonist)	Inhibits the constitutive transactivation activity of RORα	Suppresses G6PC and PCK promoter activity	Kumar et al.^107
SR2211 (Compound 49)	Ki = 105 nM (measured by radioligand binding assay, antagonist)	Affects the structural conformation of RORγ LBD	Suppresses IL17 expression, IL-17 production and TH17 cell differentiation	Kumar et al.^108
ML209 (Compound 50)	IC50 = 0.5 μM for RORγ (measured by VP16 assay, inverse agonist)	Improves stabilisation effects for the RORγ protein	Suppresses human TH17 cell differentiation	Huh et al.^109
24 (Compound 51)	EC50 = 9 nM for RORγ (measured by human RORγ luciferase (LUC) assay, inhibitor)	Improves transactivation activity of RORγ	Suppresses production of IL-17 in vivo	Kotoku et al.^110
XY101 (Compound 52)	IC50 = 30 nM for RORγ (measured by cell-based reporter gene assay, inverse agonist)	Improves transactivation activity of RORγ and stabilisation effects for the RORγ protein	Suppresses cell growth, colony formation, and expression of AR, AR-V7, and PSA	Zhang et al.^111

Table 4 Representative modulators targeting kinases.

Name	Activity	Physiological Effects	Reference
IC261 (Compound 53)	Inhibiting CK1ε	Period lengthening	Eide et al.^115
CKI-7 (Compound 54)	Inhibiting CK1ε	Period lengthening	Vanselow et al.^116
D4476 (Compound 55)	Inhibiting CK1ε	Period lengthening	Reischl et al.^120
PF-4800567 (Compound 56)	Inhibiting CK1ε	Period lengthening	Meng et al.^121
LH846 (Compound 57)	Inhibiting CK1δ	Period lengthening	Lee et al.^122
1-3 (Compound 58-60)	Inhibiting CK1ε	Period lengthening	Chen et al.^102
A002195858 (Compound 61)	Inhibiting CK1	Period lengthening	Mosser et al.^117
B-AZ (Compound 62)	Inhibiting CK1	Period lengthening	Ono et al.^118
Roscovitine (Compound 63)	Inhibiting CDK1, CDK2 and CDK5	Period lengthening	Hirota et al.^123
Puralanol A (Compound 64)	Inhibiting CDK2, CDK4 and CDK5	Period lengthening	Hirota et al.^123
Indirubin-3′-oxime (Compound 65)	Inhibiting CDK and GSK3	Period shortening	Hirota et al.^123
Kenpaullone (Compound 66)	Inhibiting CDK and GSK3	Period shortening	Hirota et al.^123
PHA767491 (Compound 67)	Inhibiting CDK7/CDK9	Period lengthening	Uehara et al.^124
Chir99021 (Compound 68)	Inhibiting GSK3β	Period shortening	Hirota et al.^123
1-azakenpaullone (Compound 69)	Inhibiting GSK3β	Period shortening	Hirota et al.^123
indirubin (Compound 70)	Inhibiting GSK3β	Period shortening	Hirota et al.^123
SB203580 (Compound 71)	Inhibiting p38	Period lengthening	Isojimaa et al.^125
PD169316 (Compound 72)	Inhibiting p38	Period lengthening	Isojimaa et al.^125
TG003 (Compound 73)	Inhibiting CLK1	Period lengthening	Isojimaa et al.^125
Nilotinib (Compound 74)	Inhibiting BCR-ABL	Period lengthening	Tamai et al.^51
Imatinib (Compound 75)	Inhibiting BCR-ABL	Period lengthening	Tamai et al.^51
Bafetinib (Compound 76)	Inhibiting BCR-ABL	Period lengthening	Tamai et al.^51

Figure 8. Development and structure of synthetic modulators targeting epigenetic proteins and others.

Table 5. Representative modulators targeting epigenetic proteins.

Name	Activity	Physiological effects	Reference
Resveratrol (Compound 77)	SIRT1 activator	Modulate physiological rhythms and clock gene expression	Chang et al.^128
SRT2183 (Compound 78)	SIRT1 activator	Reduce circadian expression Lengthen period Reduce amplitude	Bellet et al.^130
SRT1720 (Compound 79)	SIRT1 activator	Reduce circadian expression Lengthen period Reduce amplitude	Bellet et al.^130
SRTCD1023 (Compound 80)	SIRT1 activator	Reduce circadian expression Lengthen period Reduce amplitude	Bellet et al.^130
SRTCL1015 (Compound 81)	SIRT1 activator	Reduce circadian expression Lengthen period Reduce amplitude	Bellet et al.^130
Rosiglitazone (Compound 82)	PPARγ agonist	induce expression of Bmal1	Wang et al.^131
Camptothecin (Compound 83)	TOPI inhibitor	Enhance the circadian expression and lengthen the circadian period	Onishi et al.^132
Harmine (Compound 84)	TOPI inhibitor	Enhance the circadian expression	Onishi et al.^132
DHEA (Compound 85)	Androgen antagonist and oestrogen activator	Shorten the circadian period	Tamai et al.^51

Figure 9. Implications in circadian rhythm-related diseases.

Chen Z, Yoo SH, Takahashi JS. Development and therapeutic potential of small-molecule modulators of circadian systems. Annu Rev Pharmacol Toxicol 2018;58:231–52.

 PubMed Web of Science ®Google Scholar

He B, Chen Z. Molecular targets for small-molecule modulators of circadian clocks. Curr Drug Metab 2016;17:503–12.

 PubMed Web of Science ®Google Scholar

Hirota T, Lee JW, John PCS, et al. Identification of small molecule activators of cryptochrome. Science 2012;337:1094–97.

 PubMed Web of Science ®Google Scholar

Nangle S, Xing W, Zheng N. Crystal structure of mammalian cryptochrome in complex with a small molecule competitor of its ubiquitin ligase. Cell Res 2013;23:1417–19.

 PubMed Web of Science ®Google Scholar

Hirano A, Braas D, Fu Y-H, et al. FAD regulates CRYPTOCHROME protein stability and circadian clock in mice. Cell Rep 2017;19:255–66.

 PubMed Web of Science ®Google Scholar

Lee JW, Hirota T, Kumar A, et al. Development of Small-Molecule Cryptochrome Stabilizer Derivatives as Modulators of the Circadian Clock . ChemMedChem 2015;10:1489–97.

 PubMed Web of Science ®Google Scholar

Oshima T, Yamanaka I, Kumar A, et al. C-H Activation Generates Period-Shortening Molecules That Target Cryptochrome in the Mammalian Circadian Clock. Angew Chem Int Ed Engl 2015;54:7193–97.

 PubMed Web of Science ®Google Scholar

Chun SK, Jang J, Chung S, et al. Identification and validation of cryptochrome inhibitors that modulate the molecular circadian clock. ACS Chem. Biol 2014;9:703–10.

 PubMed Web of Science ®Google Scholar

Humphries PS, Bersot R, Kincaid J, et al. Carbazole-containing amides and ureas: Discovery of cryptochrome modulators as antihyperglycemic agents. Bioorg Med Chem Lett 2018;28:293–97.

 PubMed Web of Science ®Google Scholar

Miller S, Son YL, Aikawa Y, et al. Isoform-selective regulation of mammalian cryptochromes. Nat Chem Bio 2020;16:676–85.

 PubMed Web of Science ®Google Scholar

Raghuram S, Stayrook KR, Huang P, et al. Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbeta. Nat Struct Mol Biol 2007;14:1207–13.

 PubMed Web of Science ®Google Scholar

Yin L, Wu N, Curtin JC, et al. Rev-erbalpha, a heme sensor that coordinates metabolic and circadian pathways. Science 2007;318:1786–89.

 PubMed Web of Science ®Google Scholar

Meng QJ, McMaster A, Beesley S, et al. Ligand modulation of REV-ERBalpha function resets the peripheral circadian clock in a phasic manner. J Cell Sci 2008;121:3629–35.

 PubMed Web of Science ®Google Scholar

Kumar N, Solt LA, Wang Y, et al. Regulation of adipogenesis by natural and synthetic REV-ERB ligands. Endocrinology 2010;151:3015–25.

 PubMed Web of Science ®Google Scholar

Grant D, Yin L, Collins JL, et al. GSK4112, a small molecule chemical probe for the cell biology of the nuclear heme receptor Rev-erbα. ACS Chem Biol 2010;5:925–32.

 PubMed Web of Science ®Google Scholar

Solt LA, Wang Y, Banerjee S, et al. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature 2012;485:62–8.

 PubMed Web of Science ®Google Scholar

Trump RP, Bresciani S, Cooper AW, et al. Optimized chemical probes for REV-ERBα. J. Med. Chem 2013;56:4729–37.

 PubMed Web of Science ®Google Scholar

Shin Y, Noel R, Banerjee S, et al. Small molecule tertiary amines as agonists of the nuclear hormone receptor Rev-erbα. Bioorg Med Chem Lett 2012;22:4413–17.

 PubMed Web of Science ®Google Scholar

Noel R, Song X, Shin Y, et al. Synthesis and SAR of tetrahydroisoquinolines as Rev-erbα agonists. Bioorg Med Chem Lett 2012;22:3739–42.

 PubMed Web of Science ®Google Scholar

Lee J, Lee S, Chung S, et al. Identification of a novel circadian clock modulator controlling BMAL1 expression through a ROR/REV-ERB-response element-dependent mechanism. Biochem. Biophys. Res. Commun 2016;469:580–86.

 PubMed Web of Science ®Google Scholar

Kojetin D, Wang Y, Kamenecka TM, et al. Identification of SR8278, a synthetic antagonist of the nuclear heme receptor REV-ERB. ACS Chem Biol 2011;6:131–34.

 PubMed Web of Science ®Google Scholar

De Mei C, Ercolani L, Parodi C, et al. Dual inhibition of REV-ERBβ and autophagy as a novel pharmacological approach to induce cytotoxicity in cancer cells. Oncogene 2015;34:2597–2608.

 PubMed Web of Science ®Google Scholar

Torrente E, Parodi C, Ercolani L, et al. Synthesis and in vitro anticancer activity of the first class of dual inhibitors of REV-ERBβ and autophagy. J. Med. Chem 2015;58:5900–15.

 PubMedGoogle Scholar

Pariollaud M, Gibbs J, Hopwood T, et al. Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation. J Clin Invest 2018;128:2281–96.

 PubMed Web of Science ®Google Scholar

Hering Y, Berthier A, Duez H, et al. Development and implementation of a cell-based assay to discover agonists of the nuclear receptor REV-ERBα. J Biol Methods 2018;5:e94

 PubMedGoogle Scholar

Kumar N, Solt LA, Conkright JJ, et al. The benzenesulfoamide T0901317 [N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] is a novel retinoic acid receptor-related orphan receptor-alpha/gamma inverse agonist. Mol Pharmacol 2010;77:228–36.

 PubMed Web of Science ®Google Scholar

Wang Y, Kumar N, Nuhant P, et al. Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORα and RORγ. ACS Chem Biol 2010;5:1029–34.

 PubMed Web of Science ®Google Scholar

Solt LA, Kumar N, Nuhant P, et al. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 2011;472:491–4.

 PubMed Web of Science ®Google Scholar

Kumar N, Kojetin DJ, Solt LA, et al. Identification of SR3335 (ML-176): a synthetic RORα selective inverse agonist. ACS Chem. Biol 2011;6:218–22.

 PubMed Web of Science ®Google Scholar

Kumar N, Lyda B, Chang MR, et al. Identification of SR2211: a potent synthetic RORγ-selective modulator. ACS Chem. Biol 2012;7:672–77.

 PubMed Web of Science ®Google Scholar

Huh JR, Englund EE, Wang H, et al. Identification of Potent and Selective Diphenylpropanamide RORγ Inhibitors. Acs Med Chem Lett 2013;4:79–84.

 PubMed Web of Science ®Google Scholar

Kotoku M, Maeba T, Fujioka S, et al. Discovery of Second Generation RORγ Inhibitors Composed of an Azole Scaffold. J Med Chem 2019;62:2837–42.

 PubMed Web of Science ®Google Scholar

Zhang Y, Wu X, Xue X, et al. Discovery and characterization of XY101, a potent, selective, and orally bioavailable RORγ inverse agonist for treatment of castration-resistant prostate cancer. J Med Chem 2019;62:4716–30.

 PubMed Web of Science ®Google Scholar

Eide EJ, Woolf MF, Kang H, et al. Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation. Mol Cell Biol 2005;25:2795–807.

 PubMed Web of Science ®Google Scholar

Vanselow K, Vanselow JT, Westermark PO, et al. Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS). Genes Dev 2006;20:2660–72.

 PubMed Web of Science ®Google Scholar

Reischl S, Vanselow K, Westermark PO, et al. Beta-TrCP1-mediated degradation of PERIOD2 is essential for circadian dynamics. J Biol Rhythms 2007;22:375–86.

 PubMed Web of Science ®Google Scholar

Meng Q-J, Maywood ES, Bechtold DA, et al. Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes. Proc Natl Acad Sci USA 2010;107:15240–45.

 PubMed Web of Science ®Google Scholar

Lee JW, Hirota T, Peters EC, et al. A small molecule modulates circadian rhythms through phosphorylation of the period protein. Angew Chem Int Ed Engl 2011;50:10608–11.

 PubMed Web of Science ®Google Scholar

Chen Z, Yoo S-H, Park Y-S, et al. Identification of diverse modulators of central and peripheral circadian clocks by high-throughput chemical screening. Proc Natl Acad Sci USA 2012;109:101–06.

 PubMed Web of Science ®Google Scholar

Mosser EA, Chiu CN, Tamai TK, et al. Identification of pathways that regulate circadian rhythms using a larval zebrafish small molecule screen. Sci Rep 2019;9:12405

 PubMed Web of Science ®Google Scholar

Ono A, Sato A, Fujimoto KJ, et al. 3,4-Dibromo-7-Azaindole Modulates Arabidopsis Circadian Clock by Inhibiting Casein Kinase 1 Activity. Plant Cell Physiol 2019;60:2360–68.

 PubMed Web of Science ®Google Scholar

Hirota T, Lewis WG, Liu AC, et al. A chemical biology approach reveals period shortening of the mammalian circadian clock by specific inhibition of GSK-3beta. Proc Natl Acad Sci USA 2008;105:20746–51.

 PubMed Web of Science ®Google Scholar

Uehara TN, Mizutani Y, Kuwata K, et al. Casein kinase 1 family regulates PRR5 and TOC1 in the Arabidopsis circadian clock. Proc Natl Acad Sci USA 2019;116:11528–36.

 PubMed Web of Science ®Google Scholar

Isojima Y, Nakajima M, Ukai H, et al. CKIepsilon/delta-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock. Proc Natl Acad Sci USA 2009;106:15744–9.

 PubMed Web of Science ®Google Scholar

Tamai TK, Nakane Y, Ota W, et al. Identification of circadian clock modulators from existing drugs. EMBO Mol Med 2018;10:e8724.

 PubMed Web of Science ®Google Scholar

Chang HC, Guarente L. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 2013;153:1448–60.

 PubMed Web of Science ®Google Scholar

Bellet MM, Nakahata Y, Boudjelal M, et al. Pharmacological modulation of circadian rhythms by synthetic activators of the deacetylase SIRT1. Proc Natl Acad Sci USA 2013;110:3333–8.

 PubMed Web of Science ®Google Scholar

Wang N, Yang G, Jia Z, et al. Vascular PPARgamma controls circadian variation in blood pressure and heart rate through Bmal1. Cell Metab 2008;8:482–91.

 PubMed Web of Science ®Google Scholar

Onishi Y, Kawano Y. Rhythmic binding of Topoisomerase I impacts on the transcription of Bmal1 and circadian period. Nucleic Acids Res 2012;40:9482–92.

 PubMed Web of Science ®Google Scholar