Chemical Control of Mammalian Circadian Behavior through Dual Inhibition of Casein Kinase 1 alpha and delta

Abstract

Circadian rhythms are controlled by transcriptional feedback loops of clock genes and proteins. The stability of clock proteins is regulated by post-translational modification, such as phosphorylation by kinases. In particular, casein kinase I (CKI) phosphorylates the PER protein to regulate proteasomal degradation and nuclear localization. Therefore, CKI inhibition can modulate mammalian circadian rhythms. In the present study, we have developed novel CKI alpha and CKI delta dual inhibitors by extensive structural modification of N9 and C2 position of longdaysin. We identified NCC007 that showed stronger period effects (0.32 mu M for 5 h period lengthening) in a cell-based circadian assay. The following in vitro kinase assay showed that NCC007 inhibited CKI alpha and CKI delta with an IC50 of 1.8 and 3.6 mu M. We further demonstrated that NCC007 lengthened the period of mouse behavioral rhythms in vivo. Thus, NCC007 is a valuable tool compound to control circadian rhythms through CKI inhibition.