Casein kinase 1 ε (CK1ε) and casein kinase 1 δ (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. PF-4800567 is a novel and potent inhibitor of CK1ε (IC50 = 32 nM) with greater than 20-fold selectivity over CK1δ (IC50 = 711 nM). PF-4800567 effectively blocked nuclear translocation mediated by CK1ε down to 0.01 μM. Further, PF-4800567 could completely block the enhanced PER2 degradation. These data show that each of the modulatory roles that CK1ε has on the PER proteins can be potently inhibited by PF-4800567. In addition, PF-4800567 had minor effect on the circadian clock at concentrations up to 30 nM. In C57BL/6J mice, PF-4800567 (100 mg/kg, s.c.) was rapidly absorpted and distributed in plasma and brain of mice. The brain-to-plasma ratios was constant throughout the 24-h time course with an average value of 2.1. F-4800567 (100 mg/kg; dosed daily for 3days) delayed the active period by 0.5 h[1].
搜索
