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EMBO Mol Med. 2018 May;10(5). pii: e8724. doi: 10.15252/emmm.201708724.

Identification of circadian clock modulators from existing drugs.

Author information

1
Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Nagoya, Japan.
2
Laboratory of Animal Physiology, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan.
3
Department of Anatomy and Neurobiology, Kindai University Faculty of Medicine, Osaka, Japan.
4
Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto, Japan.
5
Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Nagoya, Japan takashiy@agr.nagoya-u.ac.jp.
6
Avian Bioscience Research Center, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan.
7
Division of Seasonal Biology, National Institute for Basic Biology, Okazaki, Japan.

Abstract

Chronic circadian disruption due to shift work or frequent travel across time zones leads to jet-lag and an increased risk of diabetes, cardiovascular disease, and cancer. The development of new pharmaceuticals to treat circadian disorders, however, is costly and hugely time-consuming. We therefore performed a high-throughput chemical screen of existing drugs for circadian clock modulators in human U2OS cells, with the aim of repurposing known bioactive compounds. Approximately 5% of the drugs screened altered circadian period, including the period-shortening compound dehydroepiandrosterone (DHEA; also known as prasterone). DHEA is one of the most abundant circulating steroid hormones in humans and is available as a dietary supplement in the USA Dietary administration of DHEA to mice shortened free-running circadian period and accelerated re-entrainment to advanced light-dark (LD) cycles, thereby reducing jet-lag. Our drug screen also revealed the involvement of tyrosine kinases, ABL1 and ABL2, and the BCR serine/threonine kinase in regulating circadian period. Thus, drug repurposing is a useful approach to identify new circadian clock modulators and potential therapies for circadian disorders.

KEYWORDS:

DHEA ; circadian rhythms; drug repurposing; jet‐lag; tyrosine kinases

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