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Small molecule modifiers of circadian clocks

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Abstract

Circadian clocks orchestrate 24-h oscillations of essential physiological and behavioral processes in response to daily environmental changes. These clocks are remarkably precise under constant conditions yet highly responsive to resetting signals. With the molecular composition of the core oscillator largely established, recent research has increasingly focused on clock-modifying mechanisms/molecules. In particular, small molecule modifiers, intrinsic or extrinsic, are emerging as powerful tools for understanding basic clock biology as well as developing putative therapeutic agents for clock-associated diseases. In this review, we will focus on synthetic compounds capable of modifying the period, phase, or amplitude of circadian clocks, with particular emphasis on the mammalian clock. We will discuss the potential of exploiting these small molecule modifiers in both basic and translational research.

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Fig. 1
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Abbreviations

ARNT:

Aryl hydrocarbon receptor nuclear translocator

bHLH PAS:

Basic helix–loop–helix PER-ARNT-SIM

BMAL1:

Brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like

CEM:

Clock-enhancing molecule

CLOCK:

Circadian locomotor output cycles kaput

CREB:

cAMP response element-binding protein

CRY:

Cryptochrome

FASPS:

Familial advanced sleep phase syndrome

HIF:

Hypoxia-inducible factor

NPAS2:

Neuronal PAS domain protein 2

PER:

Period

ROR:

Retinoid acid receptor-related orphan receptor

SCN:

Suprachiasmatic nuclei

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Acknowledgments

We thank J.A. Mohawk and C.C. Lee for critical reading of the manuscript, M.R. Blackburn, B. He and Y. Chelliah for helpful discussions, and N. Koike for help with literature search. Small molecules research in Z.C.’s laboratory is supported by grants from the Robert A. Welch Foundation (AU-1731), American Heart Association (11SDG7600045) and Texas Medical Center Digestive Diseases Center funded by NIH Center Grant DK56338. J.S.T. is an Investigator in the Howard Hughes Medical Institute.

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  1. Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX, 77030, USA

    Zheng Chen

  2. Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA

    Seung-Hee Yoo & Joseph S. Takahashi

  3. Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Joseph S. Takahashi

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  1. Zheng Chen
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Correspondence to Zheng Chen or Joseph S. Takahashi.

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Chen, Z., Yoo, SH. & Takahashi, J.S. Small molecule modifiers of circadian clocks. Cell. Mol. Life Sci. 70, 2985–2998 (2013). https://doi.org/10.1007/s00018-012-1207-y

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  • DOI: https://doi.org/10.1007/s00018-012-1207-y

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