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  3. 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

  • J Med Chem. 2019 Feb 28;62(4):1989-1998. doi: 10.1021/acs.jmedchem.8b01541.
Jae Wook Lee 1 2,  Tsuyoshi Hirota 3,  Daisuke Ono 4,  Sato Honma 4,  Ken-Ichi Honma 4,  Keunwan Park 5,  Steve A Kay 3 6
Affiliations

Affiliations

  • 1 Natural Product Research Center , Korea Institute of Science and Technology , Gangneung 25451 , South Korea.
  • 2 Convergence Research Center for Dementia , Korea Institute of Science and Technology , Seoul 02792 , South Korea.
  • 3 Institute of Transformative Bio-Molecules , Nagoya University , Nagoya 464-8601 , Japan.
  • 4 Department of Physiology, Graduate School of Medicine , Hokkaido University , Sapporo 060-8638 , Japan.
  • 5 Natural Product Informatics Research Center , Korea Institute of Science and Technology , Gangneung 25451 , South Korea.
  • 6 Keck School of Medicine , University of Southern California , Los Angeles , California 90089 , United States.
PMID: 30707835 DOI: 10.1021/acs.jmedchem.8b01541
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 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.

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