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].
PF-4800567 细胞实验
Cell Line
Concentration
Treated Time
Description
References
WT SCN slices
1 μM
no significant effect on circadian period
Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15240-5.
Ck1ε−/− SCN slices
1 μM
no significant effect on circadian period
Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15240-5.
Ck1εtau SCN slices
1 μM
significant lengthening of circadian period
Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15240-5.
Ck1ε−/− lung fibroblasts
1 μM
no significant lengthening of circadian period (0.3 ±0.3 h)
Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15240-5.
Ck1εtau mutant lung fibroblasts
1 μM
slight lengthening of circadian period
Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15240-5.
WT lung fibroblasts
1 μM
slight lengthening of circadian period (0.9 ±0.13 h), but no significant effect in Ck1ε−/− cells (0.3 ±0.3 h)
Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15240-5.
HT1080 cells
1 μM
7 days
Test the effect of PF4800567 on cell proliferation
Oncogene. 2011 Jun 2;30(22):2558-69.
HEK293 cells
1 μM
7 days
Test the effect of PF4800567 on cell proliferation
Oncogene. 2011 Jun 2;30(22):2558-69.
HEK293STF3A cells
1 μM
16 h
Test the inhibitory effect of PF4800567 on Wnt/β-catenin signaling
Oncogene. 2011 Jun 2;30(22):2558-69.
HEK293STF3A cells
1 μM
30 min
Test the inhibitory effect of PF4800567 on CK1ε autophosphorylation
By inhibiting CK1ε activity, the short period of CK1εTau/Tau mutant was restored to the wild-type 24 h period, revealing the critical role of CK1ε in the SCN clock.
J Neurosci. 2016 Sep 7;36(36):9326-41.
U87MG cells
28.4 μM
PF-4800567 had a modest effect on the viability of U87MG cells with an IC50 of approximately 28.4 μM
Sci Rep. 2018 Sep 11;8(1):13621.
PF-4800567 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
WT, Ck1εtau mutant, and Ck1ε−/− mice
Subcutaneous injection
100 mg/kg
Daily injections for 10 days
No significant effect on the period or phase of behavioral rhythms in WT or Ck1ε?/? mice, but significant period lengthening in Ck1εtau mutant mice
Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15240-5.
Mice
B6.B6Csnk1e and B6.D2Csnk1e mice
Intraperitoneal injection
40 mg/kg
Single administration
PF-4800567 increased methamphetamine- and fentanyl-induced locomotor activity
搜索
