Selective inhibition of casein kinase 1 epsilon minimally alters circadian clock period.
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.
Walton
Kevin M
KM
Neuroscience Discovery, Pfizer Global Research and Development, Groton, Connecticut 06340, USA.
Fisher
Katherine
K
Rubitski
David
D
Marconi
Michael
M
Meng
Qing-Jun
QJ
Sládek
Martin
M
Adams
Jessica
J
Bass
Michael
M
Chandrasekaran
Rama
R
Butler
Todd
T
Griffor
Matt
M
Rajamohan
Francis
F
Serpa
Megan
M
Chen
Yuhpyng
Y
Claffey
Michelle
M
Hastings
Michael
M
Loudon
Andrew
A
Maywood
Elizabeth
E
Ohren
Jeffrey
J
Doran
Angela
A
Wager
Travis T
TT
D000818:Animals; D048149:Casein Kinase 1 epsilon / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002940:Circadian Rhythm / Q000187:drug effects* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology
C560271:3-(3-chlorophenoxymethyl)-1-(tetrahydropyran-4-yl)-1H-pyrazolo(3,4-d)pyrimidin-4-ylamine; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C522839:PF-670462; D048149:Casein Kinase 1 epsilon