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Selective inhibition of casein kinase 1 epsilon minimally alters circadian clock period.

Authors
  • Walton, Kevin M
  • Fisher, Katherine
  • Rubitski, David
  • Marconi, Michael
  • Meng, Qing-Jun
  • Sládek, Martin
  • Adams, Jessica
  • Bass, Michael
  • Chandrasekaran, Rama
  • Butler, Todd
  • Griffor, Matt
  • Rajamohan, Francis
  • Serpa, Megan
  • Chen, Yuhpyng
  • Claffey, Michelle
  • Hastings, Michael
  • Loudon, Andrew
  • Maywood, Elizabeth
  • Ohren, Jeffrey
  • Doran, Angela
  • And 1 more
Type
Published Article
Journal
Journal of Pharmacology and Experimental Therapeutics
Publisher
American Society for Pharmacology & Experimental Therapeutics
Publication Date
Aug 01, 2009
Volume
330
Issue
2
Pages
430–439
Identifiers
DOI: 10.1124/jpet.109.151415
PMID: 19458106
Source
Medline
License
Unknown

Abstract

The circadian clock links our daily cycles of sleep and activity to the external environment. Deregulation of the clock is implicated in a number of human disorders, including depression, seasonal affective disorder, and metabolic disorders. Casein kinase 1 epsilon (CK1epsilon) and casein kinase 1 delta (CK1delta) are closely related Ser-Thr protein kinases that serve as key clock regulators as demonstrated by mammalian mutations in each that dramatically alter the circadian period. Therefore, inhibitors of CK1delta/epsilon may have utility in treating circadian disorders. Although we previously demonstrated that a pan-CK1delta/epsilon inhibitor, 4-[3-cyclohexyl-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyrimidin-2-ylamine (PF-670462), causes a significant phase delay in animal models of circadian rhythm, it remains unclear whether one of the kinases has a predominant role in regulating the circadian clock. To test this, we have characterized 3-(3-chloro-phenoxymethyl)-1-(tetrahydro-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (PF-4800567), a novel and potent inhibitor of CK1epsilon (IC(50) = 32 nM) with greater than 20-fold selectivity over CK1delta. PF-4800567 completely blocks CK1epsilon-mediated PER3 nuclear localization and PER2 degradation. In cycling Rat1 fibroblasts and a mouse model of circadian rhythm, however, PF-4800567 has only a minimal effect on the circadian clock at concentrations substantially over its CK1epsilon IC(50). This is in contrast to the pan-CK1delta/epsilon inhibitor PF-670462 that robustly alters the circadian clock under similar conditions. These data indicate that CK1epsilon is not the predominant mediator of circadian timing relative to CK1delta. PF-4800567 should prove useful in probing unique roles between these two kinases in multiple signaling pathways.

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