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Molecular Targets for Small-Molecule Modulators of Circadian Clocks

[ Vol. 17 , Issue. 5 ]

Author(s):

Baokun He and Zheng Chen   Pages 503 - 512 ( 10 )

Abstract:


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.

Keywords:

Circadian clock, drug metabolism, metabolic syndrome, molecular target, nuclear receptor, small-molecule modulator.

Affiliation:

Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, MSB 6.200, Houston, TX 77030, USA.



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