title: Selective inhibition of casein kinase 1 epsilon minimally alters circadian clock period.
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.
authors.affiliation: Neuroscience Discovery, Pfizer Global Research and Development, Groton, Connecticut 06340, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Walton
authors.forename: Katherine
authors.initials: K
authors.lastname: Fisher
authors.forename: David
authors.initials: D
authors.lastname: Rubitski
authors.forename: Michael
authors.initials: M
authors.lastname: Marconi
authors.forename: Qing-Jun
authors.initials: QJ
authors.lastname: Meng
authors.forename: Martin
authors.initials: M
authors.lastname: Sládek
authors.forename: Jessica
authors.initials: J
authors.lastname: Adams
authors.forename: Michael
authors.initials: M
authors.lastname: Bass
authors.forename: Rama
authors.initials: R
authors.lastname: Chandrasekaran
authors.forename: Todd
authors.initials: T
authors.lastname: Butler
authors.forename: Matt
authors.initials: M
authors.lastname: Griffor
authors.forename: Francis
authors.initials: F
authors.lastname: Rajamohan
authors.forename: Megan
authors.initials: M
authors.lastname: Serpa
authors.forename: Yuhpyng
authors.initials: Y
authors.lastname: Chen
authors.forename: Michelle
authors.initials: M
authors.lastname: Claffey
authors.forename: Michael
authors.initials: M
authors.lastname: Hastings
authors.forename: Andrew
authors.initials: A
authors.lastname: Loudon
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Maywood
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ohren
authors.forename: Angela
authors.initials: A
authors.lastname: Doran
authors.forename: Travis T
authors.initials: TT
authors.lastname: Wager
mesh_terms: 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
chemical_list: 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