Chemical Control of Mammalian Circadian Behavior through Dual Inhibition of Casein Kinase Iα and δ
- Chemical Control of Mammalian Circadian Behavior through Dual Inhibition of Casein Kinase Iα and δ
- 이재욱; 박근완; Tsuyoshi Hirota; Daisuke Ono; Sato Honma; Ken-ichi Honma; Steve A. Kay
- Issue Date
- Journal of medicinal chemistry
- VOL 62, NO 4-1998
- 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 cellbased 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.
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