Article

A small molecule modulates circadian rhythms through phosphorylation of the period protein.

Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Angewandte Chemie International Edition (Impact Factor: 11.34). 09/2011; 50(45):10608-11. DOI: 10.1002/anie.201103915
Source: PubMed
1 Bookmark
 · 
169 Views
  • [Show abstract] [Hide abstract]
    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.
    Cellular and Molecular Life Sciences CMLS 11/2012; · 5.62 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Physiological processes such as the sleep-wake cycle, metabolism and hormone secretion are controlled by a circadian rhythm adapted to 24 hour day-night periodicity. This circadian synchronisation is in part controlled by ambient light decreasing melatonin secretion by the pineal gland and co-ordinated by the suprachiasmatic nucleus of the hypothalamus. Peripheral cell autonomous circadian clocks controlled by the suprachiasmatic nucleus, the master regulator, exist within every cell of the body and are comprised of at least twelve genes. These include the basic helix-loop-helix /PAS domain containing transcription factors; Clock, BMal1 and Npas2 which activate transcription of the periodic genes (Per1 and Per2) and cryptochrome genes (Cry1 and Cry2). Points of coupling exist between the cellular clock and the cell cycle. Cell cycle genes which are affected by the molecular circadian clock include c-Myc, Wee1, cyclin D and p21. Therefore the rhythm of the circadian clock and cancer are interlinked. Molecular examples exist including activation of Per2 leads to c-myc overexpression and an increased tumor incidence. Mice with mutations in Cryptochrome 1 and 2 are arrhythmic (lack a circadian rhythm) and arrhythmic mice have a faster rate of growth of implanted tumors. Epidemiological finding of relevance include 'The Nurses' Health Study' where it was established that women working rotational night shifts have an increased incidence of breast cancer. Compounds that affect circadian rhythm exist with attendant future therapeutic possibilities. These include casein kinase I and a candidate small molecule KL001 that affects the degradation of cryptochrome. Theoretically the cell cycle and malignant disease may be targeted vicariously by selective alteration of the cellular molecular clock.
    Cancer letters 10/2013; · 4.86 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Circadian rhythms, biological oscillations with a period of about 24 h, are maintained by a genetically determined innate time-keeping system called the molecular circadian clockwork. Despite the physiological and clinical importance of the circadian clock, the development of small molecule modulators that directly target the core clock machinery has only been recently initiated. In the present study, we aimed to identify novel small molecule modulators influencing the molecular feedback loop of the circadian clock by applying our two-step cell-based screening strategy based on E-box-mediated transcriptional activity to test more than 1000 drug-like compounds. A derivative of 2-ethoxypropanoic acid designated as compound 15 was selected as the most promising candidate in terms of both efficacy and potency. We then performed pull-down assays with the biotinylated compound and find out that both cryptochrome (CRY)1 and 2 (CRY1/2), key negative components of the mammalian circadian clock, as molecular targets of compound 15. In accordance with the binding property, compound 15 enhanced E-box-mediated transcription in a CRY1/2-dependent manner, and more importantly, it attenuated the circadian oscillation of Per2-Luc and Bmal1-dLuc activities in cultured fibroblasts, indicating that compound 15 can functionally inhibit the effects of CRY1/2 in the molecular circadian clockwork. In conclusion, the present study describes the first novel chemical inhibitor of CRY1/2 that inhibits the repressive function of CRY1/2, thereby activating CLOCK-BMAL1-evoked E-box-mediated transcription. Further optimizations and subsequent functional studies of this compound may lead to development of efficient therapeutic strategies for a variety of physiological and metabolic disorders with circadian natures.
    ACS Chemical Biology 01/2014; · 5.44 Impact Factor

Full-text

View
36 Downloads
Available from
May 16, 2014