Identification of diverse modulators of central and peripheral circadian clocks by high-throughput chemical screening

Zheng Chen, Seung Hee Yoo, Yong Sung Park, Keon Hee Kim, Shuguang Wei, Ethan Buhr, Zeng You Ye, Hui Lin Pan, Joseph S. Takahashi

Research output: Contribution to journalArticlepeer-review

109 Scopus citations

Abstract

The circadian clock coordinates daily oscillations of essential physiological and behavioral processes. Conversely, aberrant clocks with damped amplitude and/or abnormal period have been associated with chronic diseases and aging. To search for small molecules that perturb or enhance circadian rhythms, we conducted a high-throughput screen of approximately 200,000 synthetic compounds using Per2::lucSV reporter fibroblast cells and validated 11 independent classes of molecules with Bmal1:luciferase reporter cells as well as with suprachiasmatic nucleus and peripheral tissue explants. Four compounds were found to lengthen the period in both central and peripheral clocks, including three compounds that inhibited casein kinase Iε in vitro and a unique benzodiazepine derivative acting through a non-GABA A receptor target. In addition, two compounds acutely induced Per2::lucSV reporter bioluminescence, delayed the rhythm, and increased intracellular cAMP levels, but caused rhythm damping. Importantly, five compounds shortened the period of peripheral clocks; among them, four compounds also enhanced the amplitude of central and/or peripheral reporter rhythms. Taken together, these studies highlight diverse activities of drug-like small molecules in manipulating the central and peripheral clocks. These small molecules constitute a toolbox for probing clock regulatory mechanisms and may provide putative lead compounds for treatment of clock-associated diseases.

Original languageEnglish (US)
Pages (from-to)101-106
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number1
DOIs
StatePublished - Jan 3 2012

ASJC Scopus subject areas

  • General

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