Time to target the circadian clock for drug discovery.

The circadian clock is an intracellular timekeeping device that drives daily rhythms in diverse and extensive processes throughout the body. The clock mechanism comprises a core transcription/translation negative feedback loop that is modulated by a complex set of additional interlocking feedback loops. Pharmacological manipulation of the clock may be valuable for treating many maladies including jet lag, shift work and related sleep disorders, various metabolic diseases, and cancer. We review recent identification of small-molecule clock modulators and discuss the biochemical features of the core clock that may be amenable to future drug discovery. Circadian rhythms govern many physiological processes and have been linked to diseases such as cancer and metabolic disorders. Pharmacological manipulation of circadian rhythms can have profoundly different effects depending on whether the positive or negative arm of the loop is targeted and in which direction. The biochemical features of the core circadian clock components reveal many possible avenues for pharmacological modulation. Identification of compounds that target the core circadian proteins will provide tools for further dissection of the clock mechanism and will have broad therapeutic potential. [ABSTRACT FROM AUTHOR]