Background: Circadian clocks are endogenous timing systems that regulate various aspects of mammalian
metabolism, physiology and behavior. Traditional chronotherapy refers to the administration of drugs in a defined
circadian time window to achieve optimal pharmacokinetic and therapeutic efficacies. In recent years, substantial
efforts have been dedicated to developing novel small-molecule modulators of circadian clocks.
Methods: Here, we review the recent progress in the identification of molecular targets of small-molecule clock
modulators and their efficacies in clock-related disorders. Specifically, we examine the clock components and
regulatory factors as possible molecular targets of small molecules, and we review several key clock-related disorders
as promising venues for testing the preventive/therapeutic efficacies of these small molecules. Finally, we also
discuss circadian regulation of drug metabolism.
Results: Small molecules can modulate the period, phase and/or amplitude of the circadian cycle. Core clock proteins, nuclear hormone
receptors, and clock-related kinases and other epigenetic regulators are promising molecular targets for small molecules. Through these
targets small molecules exert protective effects against clock-related disorders including the metabolic syndrome, immune disorders,
sleep disorders and cancer. Small molecules can also modulate circadian drug metabolism and response to existing therapeutics.
Conclusion: Small-molecule clock modulators target clock components or diverse cellular pathways that functionally impinge upon the
clock. Target identification of new small-molecule modulators will deepen our understanding of key regulatory nodes in the circadian
network. Studies of clock modulators will facilitate their therapeutic applications, alone or in combination, for clock-related diseases.