Targeting Cryptochromes in Chronic Diseases

The circadian clock generates 24-h molecular rhythms through transcription-translation negative feedback loops (TTFLs) and regulates daily physiological processes such as sleep-wake cycles, body temperature, hormone secretion, metabolism, and immune function. Cryptochromes (CRY1 and CRY2) are essential components of the mammalian circadian clock as the transcriptional repressors in TTFLs. Disruption of the circadian clock by shiftwork or mutations of clock genes disturbs daily physiological rhythms and poses serious risks to human health. Misregulations of CRY in humans and mice induce chronic diseases such as diabetes mellitus, sleep disorders, inflammatory diseases, and cancers. Chemical biology approaches have been applied to further elucidate molecular mechanisms of the circadian clock and to treat chronic diseases. The chemicals enable dose-dependent and reversible manipulation, forming the basis of drug development. Since 2012, about a dozen small-molecule compounds targeting CRY have been discovered, enabling the control of CRY functions. This review summarizes the roles of CRY in chronic diseases and introduces therapeutic approaches using CRY-targeting compounds. A deeper understanding of the pathology of chronic diseases and the effects of CRY-targeting compounds may lead to new circadian clock-based strategies for clinical advances.