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

Title
Chemical Control of Mammalian Circadian Behavior through Dual Inhibition of Casein Kinase Iα and δ
Authors
이재욱박근완Tsuyoshi HirotaDaisuke OnoSato HonmaKen-ichi HonmaSteve A. Kay
Issue Date
2019-02
Publisher
Journal of medicinal chemistry
Citation
VOL 62, NO 4-1998
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 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.
URI
http://pubs.kist.re.kr/handle/201004/69100
ISSN
0022-2623
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KIST Publication > Article
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