Identification of circadian clock modulators from existing drugs

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.

The importance of determining circadian parameters in pharmacological studies

“…In addition, many existing drugs may also influence circadian rhythms. Tamai et al () screened over 1,000 molecules from a Food and Drug Administration‐approved drug library and found that 5% had effects on the circadian clocks of human osteosarcoma epithelial cells (U2OS cell line). Disruptions in circadian rhythms have been associated with several disorders, including sleep (Vanselow et al, ), metabolic (Marcheva et al, ), neurodegenerative (Musiek, ), cardiovascular (Chen & Yang, ), autoimmune/inflammatory disorders (Hand et al, ), and cancer (El‐Athman, Fuhr, & Relógio, ).…”

“…In addition, many existing drugs may also influence circadian rhythms. Tamai et al (2018) screened over 1,000 molecules from a Food and Drug Administration-approved drug library and found that 5% had effects on the circadian clocks of human osteosarcoma FIGURE 1 The circadian clock system. The mammalian circadian system can be stratified into three main components: inputs from the external environment to clocks (photic and non-photic time cues), clock mechanisms (at the cellular and systemic level), and output signalling pathways that modulate physiology and behaviour.…”

Interconnection between circadian clocks and thyroid function

“…By contrast, perturbation of oncogene can induce dysregulation of circadian clock 108,109 and disrupted circadian clock gene expression is reported during thyroid nodule malignant transformation 113 . Since disruption of circadian clocks has been implicated in various diseases 137 , pharmacological modulation of the circadian clock machinery might provide a new strategy for the treatment of thyroid diseases 139 .…”

“…The disruption of circadian clocks has been implicated in various diseases, and accordingly the identification of circadian clock modulators might provide new opportunities for treatment of clock-related disorders 137 . Studies from 2018 and 2019 have demonstrated that agonists of the REV-ERB proteins are specifically lethal to cancer cells and that a selective CK2 inhibitor inhibits cancer cell growth 138,139 .…”

Nobiletin Affects Circadian Rhythms and Oncogenic Characteristics in a Cell-Dependent Manner

“…While identification of small molecules that can modulate circadian rhythms has garnered significant interest, 27 it has recently been shown that many existing therapeutic compounds also affect circadian rhythms. 28 In a similar fashion, nobiletin, which has been known for decades to elicit various beneficial health effects, has only recently been shown to alter circadian rhythms. 2,3 Circadian rhythms are 24-hour rhythmic activity cycles.…”