Identification of Circadian Clock Modulators from Existing Drugs

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2018 Apr 19

PMID 29666146

Citations 26

Authors

T Katherine Tamai

Yusuke Nakane

Wataru Ota

Akane Kobayashi

Masateru Ishiguro

Naoya Kadofusa

Keisuke Ikegami

Kazuhiro Yagita

Yasufumi Shigeyoshi

Masaki Sudo

Taeko Nishiwaki-Ohkawa

Ayato Sato

Takashi Yoshimura

Affiliations

Soon will be listed here.

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.

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