Chemical Control of Mammalian Circadian Behavior through Dual Inhibition of Casein Kinase Iα and δ

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 CKIα and CKIδ dual inhibitors
by extensive structural modification of N9 and C2 position of longdaysin.
We identified NCC007 that showed stronger period effects (0.32 μM
for 5 h period lengthening) in a cell-based circadian assay. The following
in vitro kinase assay showed that NCC007 inhibited CKIα and
CKIδ with an IC50 of 1.8 and 3.6 μM. 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.