RT Journal Article
SR Electronic
T1 Selective Inhibition of Casein Kinase 1ϵ Minimally Alters Circadian Clock Period
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 430
OP 439
DO 10.1124/jpet.109.151415
VO 330
IS 2
A1 Kevin M. Walton
A1 Katherine Fisher
A1 David Rubitski
A1 Michael Marconi
A1 Qing-Jun Meng
A1 Martin Sládek
A1 Jessica Adams
A1 Michael Bass
A1 Rama Chandrasekaran
A1 Todd Butler
A1 Matt Griffor
A1 Francis Rajamohan
A1 Megan Serpa
A1 Yuhpyng Chen
A1 Michelle Claffey
A1 Michael Hastings
A1 Andrew Loudon
A1 Elizabeth Maywood
A1 Jeffrey Ohren
A1 Angela Doran
A1 Travis T. Wager
YR 2009
UL http://jpet.aspetjournals.org/content/330/2/430.abstract
AB 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 (CK1ϵ) and casein kinase 1 delta (CK1δ) 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 CK1δ/ϵ may have utility in treating circadian disorders. Although we previously demonstrated that a pan-CK1δ/ϵ 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 CK1ϵ (IC50 = 32 nM) with greater than 20-fold selectivity over CK1δ. PF-4800567 completely blocks CK1ϵ-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 CK1ϵ IC50. This is in contrast to the pan-CK1δ/ϵ inhibitor PF-670462 that robustly alters the circadian clock under similar conditions. These data indicate that CK1ϵ is not the predominant mediator of circadian timing relative to CK1δ. PF-4800567 should prove useful in probing unique roles between these two kinases in multiple signaling pathways. The American Society for Pharmacology and Experimental Therapeutics