Lee, Jae Wook Hirota, Tsuyoshi Ono, Daisuke Honma, Sato Honma, Ken-ichi Park, Keunwan Kay, Steve A. 2024-01-19T20:33:59Z 2024-01-19T20:33:59Z 2021-09-02 2019-02-28 0022-2623 https://pubs.kist.re.kr/handle/201004/120322 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. English AMER CHEMICAL SOC CLOCK SLEEP PHOSPHORYLATION METABOLISM PHYSIOLOGY MUTATION RHYTHMS PERIOD Chemical Control of Mammalian Circadian Behavior through Dual Inhibition of Casein Kinase 1 alpha and delta Article 10.1021/acs.jmedchem.8b01541 1 JOURNAL OF MEDICINAL CHEMISTRY, v.62, no.4, pp.1989 - 1998 JOURNAL OF MEDICINAL CHEMISTRY 62 4 1989 1998 scie scopus 000460365600018 2-s2.0-85062346427 Chemistry, Medicinal Pharmacology & Pharmacy Article CLOCK SLEEP PHOSPHORYLATION METABOLISM PHYSIOLOGY MUTATION RHYTHMS PERIOD