Identification of circadian clock modulators from existing drugs

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cells, Cultured
  • Circadian Clocks / drug effects*
  • Circadian Clocks / physiology
  • Circadian Rhythm / drug effects*
  • Circadian Rhythm / physiology
  • Drug Repositioning / methods*
  • Embryo, Mammalian / cytology
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pharmaceutical Preparations / administration & dosage*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / metabolism

Substances

  • Pharmaceutical Preparations
  • Protein Kinase Inhibitors
  • Protein Kinases