Circadian timekeeping systems drive oscillatory gene expression to regulate essential cellular and physiological processes. When the systems are perturbed, pathological consequences ensue and disease risks rise. A growing number of small-molecule modulators have been reported to target circadian systems. Such small molecules, identified via high-throughput screening or derivatized from known scaffolds, have shown promise as drug candidates to improve biological timing and physiological outputs in disease models. In this review, we first briefly describe the circadian system, including the core oscillator and the cellular networks. Research progress on clock-modulating small molecules is presented, focusing on development strategies and biological efficacies. We highlight the therapeutic potential of small molecules in clock-related pathologies, including jet lag and shiftwork; various chronic diseases, particularly metabolic disease; and aging. Emerging opportunities to identify and exploit clock modulators as novel therapeutic agents are discussed.


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Literature Cited

  1. Takahashi JS. 1.  2017. Transcriptional architecture of the mammalian circadian clock. Nat. Rev. Genet. 18:164–79 [Google Scholar]
  2. Bell-Pedersen D, Cassone VM, Earnest DJ, Golden SS, Hardin PE. 2.  et al. 2005. Circadian rhythms from multiple oscillators: lessons from diverse organisms. Nat. Rev. Genet. 6:544–56 [Google Scholar]
  3. Hogenesch JB, Herzog ED. 3.  2011. Intracellular and intercellular processes determine robustness of the circadian clock. FEBS Lett 585:1427–34 [Google Scholar]
  4. Balsalobre A, Damiola F, Schibler U. 4.  1998. A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93:929–37 [Google Scholar]
  5. Balsalobre A, Marcacci L, Schibler U. 5.  2000. Multiple signaling pathways elicit circadian gene expression in cultured Rat-1 fibroblasts. Curr. Biol. 10:1291–94 [Google Scholar]
  6. Kohsaka A, Laposky AD, Ramsey KM, Estrada C, Joshu C. 6.  et al. 2007. High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab 6:414–21 [Google Scholar]
  7. Oklejewicz M, Destici E, Tamanini F, Hut RA, Janssens R, van der Horst GT. 7.  2008. Phase resetting of the mammalian circadian clock by DNA damage. Curr. Biol. 18:286–91 [Google Scholar]
  8. Woelfle MA, Ouyang Y, Phanvijhitsiri K, Johnson CH. 8.  2004. The adaptive value of circadian clocks: an experimental assessment in cyanobacteria. Curr. Biol. 14:1481–86 [Google Scholar]
  9. DeCoursey PJ. 9.  2014. Survival value of suprachiasmatic nuclei (SCN) in four wild sciurid rodents. Behav. Neurosci. 128:240–49 [Google Scholar]
  10. Gehring W, Rosbash M. 10.  2003. The coevolution of blue-light photoreception and circadian rhythms. J. Mol. Evol. 57:Suppl. 1S286–89 [Google Scholar]
  11. Chen Z, McKnight SL. 11.  2007. A conserved DNA damage response pathway responsible for coupling the cell division cycle to the circadian and metabolic cycles. Cell Cycle 6:2906–12 [Google Scholar]
  12. Edgar RS, Green EW, Zhao Y, van Ooijen G, Olmedo M. 12.  et al. 2012. Peroxiredoxins are conserved markers of circadian rhythms. Nature 485:459–64 [Google Scholar]
  13. Bass J, Lazar MA. 13.  2016. Circadian time signatures of fitness and disease. Science 354:994–99 [Google Scholar]
  14. Scheer FA, Hilton MF, Mantzoros CS, Shea SA. 14.  2009. Adverse metabolic and cardiovascular consequences of circadian misalignment. PNAS 106:4453–58 [Google Scholar]
  15. Levi F, Schibler U. 15.  2007. Circadian rhythms: mechanisms and therapeutic implications. Annu. Rev. Pharmacol. Toxicol. 47:593–628 [Google Scholar]
  16. Schroeder AM, Colwell CS. 16.  2013. How to fix a broken clock. Trends Pharmacol. Sci. 34:605–19 [Google Scholar]
  17. Wallach T, Kramer A. 17.  2015. Chemical chronobiology: toward drugs manipulating time. FEBS Lett 589:1530–38 [Google Scholar]
  18. Nohara K, Yoo SH, Chen ZJ. 18.  2015. Manipulating the circadian and sleep cycles to protect against metabolic disease. Front. Endocrinol. 6:35 [Google Scholar]
  19. Manoogian ENC, Panda S. 19.  2016. Circadian rhythms, time-restricted feeding, and healthy aging. Ageing Res. Rev. 39:59–67 [Google Scholar]
  20. Herzog ED, Hermanstyne T, Smyllie NJ, Hastings MH. 20.  2017. Regulating the suprachiasmatic nucleus (SCN) circadian clockwork: interplay between cell-autonomous and circuit-level mechanisms. Cold Spring Harb. Perspect. Biol. 9:a027706 [Google Scholar]
  21. LeGates TA, Fernandez DC, Hattar S. 21.  2014. Light as a central modulator of circadian rhythms, sleep and affect. Nat. Rev. Neurosci. 15:443–54 [Google Scholar]
  22. Colwell CS. 22.  2011. Linking neural activity and molecular oscillations in the SCN. Nat. Rev. Neurosci. 12:553–69 [Google Scholar]
  23. Liu AC, Welsh DK, Ko CH, Tran HG, Zhang EE. 23.  et al. 2007. Intercellular coupling confers robustness against mutations in the SCN circadian clock network. Cell 129:605–16 [Google Scholar]
  24. Aton SJ, Colwell CS, Harmar AJ, Waschek J, Herzog ED. 24.  2005. Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nat. Neurosci. 8:476–83 [Google Scholar]
  25. Mohawk JA, Green CB, Takahashi JS. 25.  2012. Central and peripheral circadian clocks in mammals. Annu. Rev. Neurosci. 35:445–62 [Google Scholar]
  26. Liu AC, Lewis WG, Kay SA. 26.  2007. Mammalian circadian signaling networks and therapeutic targets. Nat. Chem. Biol. 3:630–39 [Google Scholar]
  27. Yoo SH, Yamazaki S, Lowrey PL, Shimomura K, Ko CH. 27.  et al. 2004. PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. PNAS 101:5339–46 [Google Scholar]
  28. Zhang Y, Fang B, Emmett MJ, Damle M, Sun Z. 28.  et al. 2015. Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock. Science 348:1488–92 [Google Scholar]
  29. Mitsui S, Yamaguchi S, Matsuo T, Ishida Y, Okamura H. 29.  2001. Antagonistic role of E4BP4 and PAR proteins in the circadian oscillatory mechanism. Genes Dev 15:995–1006 [Google Scholar]
  30. Asher G, Gatfield D, Stratmann M, Reinke H, Dibner C. 30.  et al. 2008. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134:317–28 [Google Scholar]
  31. Nakahata Y, Kaluzova M, Grimaldi B, Sahar S, Hirayama J. 31.  et al. 2008. The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134:329–40 [Google Scholar]
  32. Bass J. 32.  2012. Circadian topology of metabolism. Nature 491:348–56 [Google Scholar]
  33. Millius A, Ueda HR. 33.  2017. Systems biology-derived discoveries of intrinsic clocks. Front. Neurol. 8:25 [Google Scholar]
  34. Storch KF, Lipan O, Leykin I, Viswanathan N, Davis FC. 34.  et al. 2002. Extensive and divergent circadian gene expression in liver and heart. Nature 417:78–83 [Google Scholar]
  35. Zhang R, Lahens NF, Ballance HI, Hughes ME, Hogenesch JB. 35.  2014. A circadian gene expression atlas in mammals: implications for biology and medicine. PNAS 111:16219–24 [Google Scholar]
  36. Papazyan R, Zhang Y, Lazar MA. 36.  2016. Genetic and epigenomic mechanisms of mammalian circadian transcription. Nat. Struct. Mol. Biol. 23:1045–52 [Google Scholar]
  37. Eckel-Mahan K, Sassone-Corsi P. 37.  2013. Epigenetic regulation of the molecular clockwork. Prog. Mol. Biol. Transl. Sci. 119:29–50 [Google Scholar]
  38. Koike N, Yoo SH, Huang HC, Kumar V, Lee C. 38.  et al. 2012. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science 338:349–54 [Google Scholar]
  39. Perelis M, Marcheva B, Ramsey KM, Schipma MJ, Hutchison AL. 39.  et al. 2015. Pancreatic β cell enhancers regulate rhythmic transcription of genes controlling insulin secretion. Science 350:aac4250 [Google Scholar]
  40. Jeong K, He B, Nohara K, Park N, Shin Y. 40.  et al. 2015. Dual attenuation of proteasomal and autophagic BMAL1 degradation in ClockΔ19/+ mice contributes to improved glucose homeostasis. Sci. Rep. 5:12801 [Google Scholar]
  41. Gallego M, Virshup DM. 41.  2007. Post-translational modifications regulate the ticking of the circadian clock. Nat. Rev. Mol. Cell Biol. 8:139–48 [Google Scholar]
  42. Kojima S, Shingle DL, Green CB. 42.  2011. Post-transcriptional control of circadian rhythms. J. Cell Sci. 124:311–20 [Google Scholar]
  43. Lamia KA, Sachdeva UM, DiTacchio L, Williams EC, Alvarez JG. 43.  et al. 2009. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326:437–40 [Google Scholar]
  44. Busino L, Bassermann F, Maiolica A, Lee C, Nolan PM. 44.  et al. 2007. SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins. Science 316:900–4 [Google Scholar]
  45. Godinho SIH, Maywood ES, Shaw L, Tucci V, Barnard AR. 45.  et al. 2007. The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period. Science 316:897–900 [Google Scholar]
  46. Siepka SM, Yoo SH, Park J, Song W, Kumar V. 46.  et al. 2007. Circadian mutant Overtime reveals F-box protein FBXL3 regulation of Cryptochrome and Period gene expression. Cell 129:1011–23 [Google Scholar]
  47. Yoo SH, Mohawk JA, Siepka SM, Shan Y, Huh SK. 47.  et al. 2013. Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm. Cell 152:1091–105 [Google Scholar]
  48. Hirano A, Yumimoto K, Tsunematsu R, Matsumoto M, Oyama M. 48.  et al. 2013. FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes. Cell 152:1106–18 [Google Scholar]
  49. Brown SA, Pagani L, Cajochen C, Eckert A. 49.  2011. Systemic and cellular reflections on ageing and the circadian oscillator: a mini-review. Gerontology 57:427–34 [Google Scholar]
  50. Gloston G, Yoo S, Chen Z. 50.  2017. Clock-enhancing small molecules and potential applications in chronic diseases and aging. Front. Neurol. 8:100 [Google Scholar]
  51. Landgraf D, Wang LL, Diemer T, Welsh DK. 51.  2016. NPAS2 compensates for loss of CLOCK in peripheral circadian oscillators. PLOS Genet 12:e1005882 [Google Scholar]
  52. Bertolucci C, Cavallari N, Colognesi I, Aguzzi J, Chen Z. 52.  et al. 2008. Evidence for an overlapping role of CLOCK and NPAS2 transcription factors in liver circadian oscillators. Mol. Cell. Biol. 28:3070–75 [Google Scholar]
  53. DeBruyne JP, Weaver DR, Reppert SM. 53.  2007. CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock. Nat. Neurosci. 10:543–45 [Google Scholar]
  54. Zhao X, Hirota T, Han X, Cho H, Chong LW. 54.  et al. 2016. Circadian amplitude regulation via FBXW7-targeted REV-ERBα degradation. Cell 165:1644–57 [Google Scholar]
  55. Welsh DK, Yoo SH, Liu AC, Takahashi JS, Kay SA. 55.  2004. Bioluminescence imaging of individual fibroblasts reveals persistent, independently phased circadian rhythms of clock gene expression. Curr. Biol. 14:2289–95 [Google Scholar]
  56. Ko CH, Yamada YR, Welsh DK, Buhr ED, Liu AC. 56.  et al. 2010. Emergence of noise-induced oscillations in the central circadian pacemaker. PLOS Biol 8:e1000513 [Google Scholar]
  57. Lee Y, Chen R, Lee HM, Lee C. 57.  2011. Stoichiometric relationship among clock proteins determines robustness of circadian rhythms. J. Biol. Chem. 286:7033–42 [Google Scholar]
  58. Zhu B, Gates LA, Stashi E, Dasgupta S, Gonzales N. 58.  et al. 2015. Coactivator-dependent oscillation of chromatin accessibility dictates circadian gene amplitude via REV-ERB loading. Mol. Cell 60:769–83 [Google Scholar]
  59. Kojetin DJ, Burris TP. 59.  2014. REV-ERB and ROR nuclear receptors as drug targets. Nat. Rev. Drug Discov. 13:197–216 [Google Scholar]
  60. Farrow SN, Solari R, Willson TM. 60.  2012. The importance of chronobiology to drug discovery. Expert Opin. Drug Discov. 7:535–41 [Google Scholar]
  61. Chen Z, Yoo SH, Takahashi JS. 61.  2013. Small molecule modifiers of circadian clocks. Cell Mol. Life Sci. 70:2985–98 [Google Scholar]
  62. Hirota T, Lewis WG, Liu AC, Lee JW, Schultz PG, Kay SA. 62.  2008. A chemical biology approach reveals period shortening of the mammalian circadian clock by specific inhibition of GSK-3β. PNAS 105:20746–51 [Google Scholar]
  63. Isojima Y, Nakajima M, Ukai H, Fujishima H, Yamada RG. 63.  et al. 2009. CKIε/δ-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock. PNAS 106:15744–49 [Google Scholar]
  64. Hirota T, Lee JW, Lewis WG, Zhang EE, Breton G. 64.  et al. 2010. High-throughput chemical screen identifies a novel potent modulator of cellular circadian rhythms and reveals CKIα as a clock regulatory kinase. PLOS Biol 8:e1000559 [Google Scholar]
  65. Hirota T, Lee JW, St John PC, Sawa M, Iwaisako K. 65.  et al. 2012. Identification of small molecule activators of cryptochrome. Science 337:1094–97 [Google Scholar]
  66. Chen Z, Yoo SH, Park YS, Kim KH, Wei S. 66.  et al. 2012. Identification of diverse modulators of central and peripheral circadian clocks by high-throughput chemical screening. PNAS 109:101–6 [Google Scholar]
  67. Yagita K, Yamanaka I, Koinuma S, Shigeyoshi Y, Uchiyama Y. 67.  2009. Mini screening of kinase inhibitors affecting period-length of mammalian cellular circadian clock. Acta Histochem. Cytochem. 42:89–93 [Google Scholar]
  68. He B, Nohara K, Park N, Park YS, Guillory B. 68.  et al. 2016. The small molecule nobiletin targets the molecular oscillator to enhance circadian rhythms and protect against metabolic syndrome. Cell Metab 23:610–21 [Google Scholar]
  69. Hu Y, Spengler ML, Kuropatwinski KK, Comas-Soberats M, Jackson M. 69.  et al. 2011. Selenium is a modulator of circadian clock that protects mice from the toxicity of a chemotherapeutic drug via upregulation of the core clock protein, BMAL1. Oncotarget 2:1279–90 [Google Scholar]
  70. Chun SK, Jang J, Chung S, Yun H, Kim NJ. 70.  et al. 2014. Identification and validation of cryptochrome inhibitors that modulate the molecular circadian clock. ACS Chem. Biol. 9:703–10 [Google Scholar]
  71. Grant D, Yin L, Collins JL, Parks DJ, Orband-Miller LA. 71.  et al. 2010. GSK4112, a small molecule chemical probe for the cell biology of the nuclear heme receptor Rev-erbα. ACS Chem. Biol. 5:925–32 [Google Scholar]
  72. Humphries PS, Bersot R, Kincaid J, Mabery E, McCluskie K. 72.  et al. 2016. Carbazole-containing sulfonamides and sulfamides: discovery of cryptochrome modulators as antidiabetic agents. Bioorg. Med. Chem. Lett. 26:757–60 [Google Scholar]
  73. Walton KM, Fisher K, Rubitski D, Marconi M, Meng QJ. 73.  et al. 2009. Selective inhibition of casein kinase 1 epsilon minimally alters circadian clock period. J. Pharmacol. Exp. Ther. 330:430–39 [Google Scholar]
  74. Badura L, Swanson T, Adamowicz W, Adams J, Cianfrogna J. 74.  et al. 2007. An inhibitor of casein kinase Iε induces phase delays in circadian rhythms under free-running and entrained conditions. J. Pharmacol. Exp. Ther. 322:730–38 [Google Scholar]
  75. Meng QJ, Maywood ES, Bechtold DA, Lu WQ, Li J. 75.  et al. 2010. Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes. PNAS 107:15240–45 [Google Scholar]
  76. Solt LA, Wang Y, Banerjee S, Hughes T, Kojetin DJ. 76.  et al. 2012. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature 485:62–68 [Google Scholar]
  77. Antoch MP, Kondratov RV. 77.  2013. Pharmacological modulators of the circadian clock as potential therapeutic drugs: focus on genotoxic/anticancer therapy. Handb. Exp. Pharmacol. 217:289–309 [Google Scholar]
  78. He B, Chen Z. 78.  2016. Molecular targets for small-molecule modulators of circadian clocks. Curr. Drug Metab. 17:503–12 [Google Scholar]
  79. Trump RP, Bresciani S, Cooper AW, Tellam JP, Wojno J. 79.  et al. 2013. Optimized chemical probes for REV-ERBα. J. Med. Chem. 56:4729–37 [Google Scholar]
  80. Nangle S, Xing W, Zheng N. 80.  2013. Crystal structure of mammalian cryptochrome in complex with a small molecule competitor of its ubiquitin ligase. Cell Res 23:1417–19 [Google Scholar]
  81. Jones KA, Hatori M, Mure LS, Bramley JR, Artymyshyn R. 81.  et al. 2013. Small-molecule antagonists of melanopsin-mediated phototransduction. Nat. Chem. Biol. 9:630–35 [Google Scholar]
  82. Kon N, Hirota T, Kawamoto T, Kato Y, Tsubota T, Fukada Y. 82.  2008. Activation of TGF-β/activin signalling resets the circadian clock through rapid induction of Dec1 transcripts. Nat. Cell Biol. 10:1463–69 [Google Scholar]
  83. Shim HS, Kim H, Lee J, Son GH, Cho S. 83.  et al. 2007. Rapid activation of CLOCK by Ca2+-dependent protein kinase C mediates resetting of the mammalian circadian clock. EMBO Rep 8:366–71 [Google Scholar]
  84. Meng QJ, McMaster A, Beesley S, Lu WQ, Gibbs J. 84.  et al. 2008. Ligand modulation of REV-ERBα function resets the peripheral circadian clock in a phasic manner. J. Cell Sci. 121:3629–35 [Google Scholar]
  85. Gibbs JE, Blaikley J, Beesley S, Matthews L, Simpson KD. 85.  et al. 2012. The nuclear receptor REV-ERBα mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines. PNAS 109:582–87 [Google Scholar]
  86. Asher G, Schibler U. 86.  2011. Crosstalk between components of circadian and metabolic cycles in mammals. Cell Metab 13:125–37 [Google Scholar]
  87. Rutter J, Reick M, McKnight SL. 87.  2002. Metabolism and the control of circadian rhythms. Annu. Rev. Biochem. 71:307–31 [Google Scholar]
  88. Green CB, Takahashi JS, Bass J. 88.  2008. The meter of metabolism. Cell 134:728–42 [Google Scholar]
  89. Harfmann BD, Schroder EA, Kachman MT, Hodge BA, Zhang X, Esser KA. 89.  2016. Muscle-specific loss of Bmal1 leads to disrupted tissue glucose metabolism and systemic glucose homeostasis. Skeletal Muscle 6:12 [Google Scholar]
  90. Peek CB, Affinati AH, Ramsey KM, Kuo HY, Yu W. 90.  et al. 2013. Circadian clock NAD+ cycle drives mitochondrial oxidative metabolism in mice. Science 342:1243417 [Google Scholar]
  91. Jetten AM, Kang HS, Takeda Y. 91.  2013. Retinoic acid-related orphan receptors α and γ: key regulators of lipid/glucose metabolism, inflammation, and insulin sensitivity. Front. Endocrinol. 4:1 [Google Scholar]
  92. Chang MR, He Y, Khan TM, Kuruvilla DS, Garcia-Ordonez R. 92.  et al. 2015. Antiobesity effect of a small molecule repressor of RORγ. Mol. Pharmacol. 88:48–56 [Google Scholar]
  93. Kumar N, Kojetin DJ, Solt LA, Kumar KG, Nuhant P. 93.  et al. 2011. Identification of SR3335 (ML-176): a synthetic RORα selective inverse agonist. ACS Chem. Biol. 6:218–22 [Google Scholar]
  94. Wang Y, Kumar N, Nuhant P, Cameron MD, Istrate MA. 94.  et al. 2010. Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORα and RORγ. ACS Chem. Biol. 5:1029–34 [Google Scholar]
  95. Zhang EE, Liu Y, Dentin R, Pongsawakul PY, Liu AC. 95.  et al. 2010. Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nat. Med. 16:1152–56 [Google Scholar]
  96. Boden G, Chen X, Polansky M. 96.  1999. Disruption of circadian insulin secretion is associated with reduced glucose uptake in first-degree relatives of patients with type 2 diabetes. Diabetes 48:2182–88 [Google Scholar]
  97. Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G. 97.  et al. 2005. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308:1043–45 [Google Scholar]
  98. Pendergast JS, Branecky KL, Yang W, Ellacott KL, Niswender KD, Yamazaki S. 98.  2013. High-fat diet acutely affects circadian organisation and eating behavior. Eur. J. Neurosci. 37:1350–56 [Google Scholar]
  99. Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA. 99.  et al. 2012. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab 15:848–60 [Google Scholar]
  100. Mulvihill EE, Burke AC, Huff MW. 100.  2016. Citrus flavonoids as regulators of lipoprotein metabolism and atherosclerosis. Annu. Rev. Nutr. 36:275–99 [Google Scholar]
  101. Nohara K, Shin Y, Park N, Jeong K, He B. 101.  et al. 2015. Ammonia-lowering activities and carbamoyl phosphate synthetase 1 (Cps1) induction mechanism of a natural flavonoid. Nutr. Metab. 12:23 [Google Scholar]
  102. Shinozaki A, Misawa K, Ikeda Y, Haraguchi A, Kamagata M. 102.  et al. 2017. Potent effects of flavonoid nobiletin on amplitude, period, and phase of the circadian clock rhythm in PER2::LUCIFERASE mouse embryonic fibroblasts. PLOS ONE 12:e0170904 [Google Scholar]
  103. Bass J. 103.  2016. Targeting time in metabolic therapeutics. Cell Metab 23:575–77 [Google Scholar]
  104. Solt LA, Banerjee S, Campbell S, Kamenecka TM, Burris TP. 104.  2015. ROR inverse agonist suppresses insulitis and prevents hyperglycemia in a mouse model of type 1 diabetes. Endocrinology 156:869–81 [Google Scholar]
  105. Xiao S, Yosef N, Yang J, Wang Y, Zhou L. 105.  et al. 2014. Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity 40:477–89 [Google Scholar]
  106. Knight ZA, Shokat KM. 106.  2007. Chemical genetics: where genetics and pharmacology meet. Cell 128:425–30 [Google Scholar]
  107. Lau P, Fitzsimmons RL, Raichur S, Wang SCM, Lechtken A, Muscat GEO. 107.  2008. The orphan nuclear receptor, RORα, regulates gene expression that controls lipid metabolism: staggerer (SG/SG) mice are resistant to diet-induced obesity. J. Biol. Chem. 283:18411–21 [Google Scholar]
  108. Pevet P, Challet E. 108.  2011. Melatonin: both master clock output and internal time-giver in the circadian clocks network. J. Physiol. Paris 105:170–82 [Google Scholar]
  109. Yamaguchi Y, Suzuki T, Mizoro Y, Kori H, Okada K. 109.  et al. 2013. Mice genetically deficient in vasopressin V1a and V1b receptors are resistant to jet lag. Science 342:85–90 [Google Scholar]
  110. Sehgal A, Mignot E. 110.  2011. Genetics of sleep and sleep disorders. Cell 146:194–207 [Google Scholar]
  111. Jones CR, Huang AL, Ptacek LJ, Fu YH. 111.  2013. Genetic basis of human circadian rhythm disorders. Exp. Neurol. 243:28–33 [Google Scholar]
  112. Funato H, Miyoshi C, Fujiyama T, Kanda T, Sato M. 112.  et al. 2016. Forward-genetics analysis of sleep in randomly mutagenized mice. Nature 539:378–83 [Google Scholar]
  113. Pizarro A, Hayer K, Lahens NF, Hogenesch JB. 113.  2013. CircaDB: a database of mammalian circadian gene expression profiles. Nucleic Acids Res 41:D1009–13 [Google Scholar]
  114. Man K, Loudon A, Chawla A. 114.  2016. Immunity around the clock. Science 354:999–1003 [Google Scholar]
  115. Huh JR, Leung MWL, Huang P, Ryan DA, Krout MR. 115.  et al. 2011. Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity. Nature 472:486–90 [Google Scholar]
  116. Xu T, Wang X, Zhong B, Nurieva RI, Ding S, Dong C. 116.  2011. Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORγt protein. J. Biol. Chem. 286:22707–10 [Google Scholar]
  117. Solt LA, Kumar N, Nuhant P, Wang Y, Lauer JL. 117.  et al. 2011. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 472:491–94 [Google Scholar]
  118. Kumar N, Solt LA, Conkright JJ, Wang Y, Istrate MA. 118.  et al. 2010. 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-α/γ inverse agonist. Mol. Pharmacol. 77:228–36 [Google Scholar]
  119. McClung CA. 119.  2007. Circadian genes, rhythms and the biology of mood disorders. Pharmacol. Ther. 114:222–32 [Google Scholar]
  120. Bedrosian TA, Nelson RJ. 120.  2013. Sundowning syndrome in aging and dementia: research in mouse models. Exp. Neurol. 243:67–73 [Google Scholar]
  121. Magnusson A, Boivin D. 121.  2003. Seasonal affective disorder: an overview. Chronobiol. Int. 20:189–207 [Google Scholar]
  122. Souetre E, Salvati E, Belugou JL, Pringuey D, Candito M. 122.  et al. 1989. Circadian rhythms in depression and recovery: evidence for blunted amplitude as the main chronobiological abnormality. Psychiatry Res 28:263–78 [Google Scholar]
  123. Roybal K, Theobold D, Graham A, DiNieri JA, Russo SJ. 123.  et al. 2007. Mania-like behavior induced by disruption of CLOCK. PNAS 104:6406–11 [Google Scholar]
  124. Ikeda Y, Kumagai H, Skach A, Sato M, Yanagisawa M. 124.  2013. Modulation of circadian glucocorticoid oscillation via adrenal opioid-CXCR7 signaling alters emotional behavior. Cell 155:1323–36 [Google Scholar]
  125. Li J, Lu WQ, Beesley S, Loudon AS, Meng QJ. 125.  2012. Lithium impacts on the amplitude and period of the molecular circadian clockwork. PLOS ONE 7:e33292 [Google Scholar]
  126. Yin L, Wang J, Klein PS, Lazar MA. 126.  2006. Nuclear receptor Rev-erbα is a critical lithium-sensitive component of the circadian clock. Science 311:1002–5 [Google Scholar]
  127. Banerjee S, Wang Y, Solt LA, Griffett K, Kazantzis M. 127.  et al. 2014. Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour. Nat. Commun. 5:5759 [Google Scholar]
  128. Chung S, Lee EJ, Yun S, Choe HK, Park SB. 128.  et al. 2014. Impact of circadian nuclear receptor REV-ERBα on midbrain dopamine production and mood regulation. Cell 157:858–68 [Google Scholar]
  129. Son GH, Chung S, Ramirez VD, Kim K. 129.  2016. Pharmacological modulators of molecular clock and their therapeutic potentials in circadian rhythm-related diseases. Med. Chem. 6:724–33 [Google Scholar]
  130. Sellix MT, Evans JA, Leise TL, Castanon-Cervantes O, Hill DD. 130.  et al. 2012. Aging differentially affects the re-entrainment response of central and peripheral circadian oscillators. J. Neurosci. 32:16193–202 [Google Scholar]
  131. Banks G, Nolan PM, Peirson SN. 131.  2016. Reciprocal interactions between circadian clocks and aging. Mamm. Genome 27:332–40 [Google Scholar]
  132. Miyazaki M, Schroder E, Edelmann SE, Hughes ME, Kornacker K. 132.  et al. 2011. Age-associated disruption of molecular clock expression in skeletal muscle of the spontaneously hypertensive rat. PLOS ONE 6:e27168 [Google Scholar]
  133. Luo W, Chen WF, Yue Z, Chen D, Sowcik M. 133.  et al. 2012. Old flies have a robust central oscillator but weaker behavioral rhythms that can be improved by genetic and environmental manipulations. Aging Cell 11:428–38 [Google Scholar]
  134. Kondratov RV, Kondratova AA, Gorbacheva VY, Vykhovanets OV, Antoch MP. 134.  2006. Early aging and age-related pathologies in mice deficient in BMAL1, the core component of the circadian clock. Genes Dev 20:1868–73 [Google Scholar]
  135. Gutman R, Genzer Y, Chapnik N, Miskin R, Froy O. 135.  2011. Long-lived mice exhibit 24 h locomotor circadian rhythms at young and old age. Exp. Gerontol. 46:606–9 [Google Scholar]
  136. Longo VD, Panda S. 136.  2016. Fasting, circadian rhythms, and time-restricted feeding in healthy lifespan. Cell Metab 23:1048–59 [Google Scholar]
  137. Tevy MF, Giebultowicz J, Pincus Z, Mazzoccoli G, Vinciguerra M. 137.  2013. Aging signaling pathways and circadian clock-dependent metabolic derangements. Trends Endocrinol. Metab. 24:229–37 [Google Scholar]
  138. Katewa SD, Akagi K, Bose N, Rakshit K, Camarella T. 138.  et al. 2016. Peripheral circadian clocks mediate dietary restriction-dependent changes in lifespan and fat metabolism in Drosophila. Cell Metab 23:143–54 [Google Scholar]
  139. Finkel T. 139.  2015. The metabolic regulation of aging. Nat. Med. 21:1416–23 [Google Scholar]
  140. Chang HC, Guarente L. 140.  2013. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 153:1448–60 [Google Scholar]
  141. Hubbard BP, Sinclair DA. 141.  2014. Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol. Sci. 35:146–54 [Google Scholar]
  142. Pifferi F, Dal-Pan A, Languille S, Aujard F. 142.  2013. Effects of resveratrol on daily rhythms of locomotor activity and body temperature in young and aged grey mouse lemurs. Oxidative Med. Cell. Longev. 2013:187301 [Google Scholar]
  143. Bellet MM, Nakahata Y, Boudjelal M, Watts E, Mossakowska DE. 143.  et al. 2013. Pharmacological modulation of circadian rhythms by synthetic activators of the deacetylase SIRT1. PNAS 110:3333–38 [Google Scholar]
  144. Stehlin C, Wurtz JM, Steinmetz A, Greiner E, Schüle R. 144.  et al. 2001. X-ray structure of the orphan nuclear receptor RORβ ligand-binding domain in the active conformation. EMBO J 20:5822–31 [Google Scholar]
  145. Xing W, Busino L, Hinds TR, Marionni ST, Saifee NH. 145.  et al. 2013. SCFFBXL3 ubiquitin ligase targets cryptochromes at their cofactor pocket. Nature 496:64–68 [Google Scholar]
  146. Huang N, Chelliah Y, Shan Y, Taylor CA, Yoo SH. 146.  et al. 2012. Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex. Science 337:189–94 [Google Scholar]
  147. Wu D, Su X, Potluri N, Kim Y, Rastinejad F. 147.  2016. NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors. eLife 5:e18790 [Google Scholar]
  148. Key J, Scheuermann TH, Anderson PC, Daggett V, Gardner KH. 148.  2009. Principles of ligand binding within a completely buried cavity in HIF2α PAS-B. J. Am. Chem. Soc. 131:17647–54 [Google Scholar]
  149. McIntosh BE, Hogenesch JB, Bradfield CA. 149.  2010. Mammalian Per-Arnt-Sim proteins in environmental adaptation. Annu. Rev. Physiol. 72:625–45 [Google Scholar]
  150. Arkin MR, Tang Y, Wells JA. 150.  2014. Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Chem. Biol. 21:1102–14 [Google Scholar]
  151. Laraia L, McKenzie G, Spring DR, Venkitaraman AR, Huggins DJ. 151.  2015. Overcoming chemical, biological, and computational challenges in the development of inhibitors targeting protein-protein interactions. Chem. Biol. 22:689–703 [Google Scholar]
  152. Nangle SN, Rosensweig C, Koike N, Tei H, Takahashi JS. 152.  et al. 2014. Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex. eLife 3:e03674 [Google Scholar]
  153. Tsimakouridze EV, Alibhai FJ, Martino TA. 153.  2015. Therapeutic applications of circadian rhythms for the cardiovascular system. Front. Pharmacol. 6:77 [Google Scholar]
  154. Doi M, Takahashi Y, Komatsu R, Yamazaki F, Yamada H. 154.  et al. 2010. Salt-sensitive hypertension in circadian clock–deficient Cry-null mice involves dysregulated adrenal Hsd3b6. Nat. Med. 16:67–74 [Google Scholar]
  155. Jeyaraj D, Haldar SM, Wan X, McCauley MD, Ripperger JA. 155.  et al. 2012. Circadian rhythms govern cardiac repolarization and arrhythmogenesis. Nature 483:96–99 [Google Scholar]
  156. Papagiannakopoulos T, Bauer MR, Davidson SM, Heimann M, Subbaraj L. 156.  et al. 2016. Circadian rhythm disruption promotes lung tumorigenesis. Cell Metab 24:324–31 [Google Scholar]
  157. Fu L, Lee CC. 157.  2003. The circadian clock: pacemaker and tumour suppressor. Nat. Rev. Cancer 3:350–61 [Google Scholar]
  158. Kettner NM, Voicu H, Finegold MJ, Coarfa C, Sreekumar A. 158.  et al. 2016. Circadian homeostasis of liver metabolism suppresses hepatocarcinogenesis. Cancer Cell 30:909–24 [Google Scholar]
  159. Kondratova AA, Kondratov RV. 159.  2012. The circadian clock and pathology of the ageing brain. Nat. Rev. Neurosci. 13:325–35 [Google Scholar]
  160. Oshima T, Yamanaka I, Kumar A, Yamaguchi J, Nishiwaki-Ohkawa T. 160.  et al. 2015. C-H activation generates period-shortening molecules that target cryptochrome in the mammalian circadian clock. Angew. Chem. Int. Ed. Engl. 54:7193–97 [Google Scholar]
  161. Chun SK, Chung S, Kim HD, Lee JH, Jang J. 161.  et al. 2015. A synthetic cryptochrome inhibitor induces anti-proliferative effects and increases chemosensitivity in human breast cancer cells. Biochem. Biophys. Res. Commun. 467:441–46 [Google Scholar]
  162. Vieira E, Marroquí L, Figueroa ALC, Merino B, Fernandez-Ruiz R. 162.  et al. 2013. Involvement of the clock gene Rev-erb alpha in the regulation of glucagon secretion in pancreatic alpha-cells. PLOS ONE 8:e69939 [Google Scholar]
  163. De Mei C Ercolani L, Parodi C, Veronesi M, Lo Vecchio C. 163.  et al. 2015. Dual inhibition of REV-ERBβ and autophagy as a novel pharmacological approach to induce cytotoxicity in cancer cells. Oncogene 34:2597–608 [Google Scholar]
  164. Wang Y, Billon C, Walker JK, Burris TP. 164.  2016. Therapeutic effect of a synthetic RORα/γ agonist in an animal model of autism. ACS Chem. Neurosci. 7:143–48 [Google Scholar]
  165. Byun JK, Choi YK, Kang YN, Jang BK, Kang KJ. 165.  et al. 2015. Retinoic acid-related orphan receptor alpha reprograms glucose metabolism in glutamine-deficient hepatoma cells. Hepatology 61:953–64 [Google Scholar]
  166. Helleboid S, Haug C, Lamottke K, Zhou Y, Wei J. 166.  et al. 2014. The identification of naturally occurring neoruscogenin as a bioavailable, potent, and high-affinity agonist of the nuclear receptor RORα (NR1F1). J. Biomol. Screen. 19:399–406 [Google Scholar]
  167. Zhang W, Zhang J, Fang L, Zhou L, Wang S. 167.  et al. 2012. Increasing human Th17 differentiation through activation of orphan nuclear receptor retinoid acid-related orphan receptor γ (RORγ) by a class of aryl amide compounds. Mol. Pharmacol. 82:583–90 [Google Scholar]
  168. Barnea M, Haviv L, Gutman R, Chapnik N, Madar Z, Froy O. 168.  2012. Metformin affects the circadian clock and metabolic rhythms in a tissue-specific manner. Biochim. Biophys. Acta 1822:1796–806 [Google Scholar]
  169. Maier B, Wendt S, Vanselow JT, Wallach T, Reischl S. 169.  et al. 2009. A large-scale functional RNAi screen reveals a role for CK2 in the mammalian circadian clock. Genes Dev 23:708–18 [Google Scholar]
  170. Iwahana E, Akiyama M, Miyakawa K, Uchida A, Kasahara J. 170.  et al. 2004. Effect of lithium on the circadian rhythms of locomotor activity and glycogen synthase kinase-3 protein expression in the mouse suprachiasmatic nuclei. Eur. J. Neurosci. 19:2281–87 [Google Scholar]
  171. Yao H, Sundar IK, Huang Y, Gerloff J, Sellix MT. 171.  et al. 2015. Disruption of sirtuin 1–mediated control of circadian molecular clock and inflammation in chronic obstructive pulmonary disease. Am. J. Respir. Cell Mol. Biol. 53:782–92 [Google Scholar]

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