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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: 11.26). 11/2011; 50(45):10608-11. DOI: 10.1002/anie.201103915
Source: PubMed

ABSTRACT

Time shift: A high-throughput cell-based screen identified a benzothiazole analogue, LH846, which induces period lengthening of the circadian rhythm. Affinity chromatography coupled with mass spectrometry and genomic analysis identified protein kinase CKIδ as the biological target of LH846 (see picture).

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    • "For example, heme [9], cAMP [10], and NAD [11] have been shown to affect the periodicity of the molecular circadian clock. Casein kinase I inhibitors such as longdaysin [12] and LH846 [13] were also shown to change the circadian period. More recently, small molecules directly targeting core clock components have been developed; synthetic ligands of REV-ERBs, including GSK4112, SR8278, SR9009, and SR9011 [14e16] were developed as promising molecular clock modulators. "
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    • "Kinase and phosphatase-mediated posttranslational modifications provide an additional layer of regulation for clock proteins. For example, nuclear entry of PER and CRY is regulated via phosphorylation by Casein Kinase 1 isoforms δ/ε (CK1δ/ε) (Badura et al., 2007;Lee et al., 2011). The molecular circadian clock mediates the regulation of rhythmic physiological function via transcriptional control and posttranscriptional control of downstream clock target genes, and this regulation occurs in a tissue-specific manner. "
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