CK1 kinases regulate diverse processes including Wnt signaling, membrane trafficking, the actin cytoskeleton, the DNA damage response, and circadian rhythms. Importantly, aberrant CK1δ and CK1ε activity is implicated in human pathologies, including neurodegenerative diseases, sleep disorders and cancer. PF-670462 is an effective and selective CK1ε and CK1δ inhibitor with IC50s of 90 nM and 13 nM, respectively[3]. A549 cells were treated with transforming growth factor-beta (TGF-β) (100 pM) for 48 h with PF670462 added 30 min prior to TGF-β. PF670462 concentration-dependently inhibited TGF-β-induced loss of E-cadherin expression, reaching a maximum effect at 3-10 μM PF670462. PF670462 (30 mg/kg/day, i.p.) attenuated bleomycin-induced accumulation of hydroxyproline and the number of infiltrating immune cells measured in the BAL fluid. In a separate study in female mice, aerosolised PF670462 (0.3-3.0 mg/ml, 15 min/once daily) corresponding to estimated deposited doses of ∼1-10 μg/day from day 8-20, also reduced hydroxyproline content, BALF cell influx, and fibrogenic gene expression at day 21[4].
Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15240-5.
SCN slices
1 μM
PF-670462 significantly lengthened the circadian period in SCN slices and eventually led to arrhythmia.
Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15240-5.
lung fibroblasts
1 μM
PF-670462 significantly lengthened the circadian period in WT, Ck1εtau, and Ck1ε−/− derived lung fibroblasts.
Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15240-5.
BEAS-2B cells
1 μM and 10 μM
30 min
PF-670462 dose-dependently prevented TGF-β1-induced E-cadherin loss and collagen I gain, indicating that δ- and ε-isoforms of casein kinase I and AKAPs distinctly regulate the TGF-β1-induced EMT in BEAS-2B cells.
Cells. 2020 Feb 3;9(2):356.
HT1080 cells
1 µM
7 days
PF-670462 only modestly reduced cell growth and did not induce cell cycle arrest or apoptosis
Oncogene. 2011 Jun 2;30(22):2558-69.
HEK293 cells
1 µM
7 days
PF-670462 only modestly reduced cell growth and did not induce cell cycle arrest or apoptosis
Oncogene. 2011 Jun 2;30(22):2558-69.
PF-670462 2HCl 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
CD-1 mice
Intraperitoneal injection
25 µM
Single injection, lasting 24 hours
To evaluate the protective effect of PF-670462 on CDDP-induced oocyte apoptosis. PF-670462 effectively blocked cisplatin-induced oocyte death, indicating that CK1-mediated phosphorylation is essential for TAp63 αactivation, even in the absence of tetramer formation.
Cell Death Dis. 2024 Nov 7;15(11):799.
Mice
WT, Ck1εtau, and Ck1ε−/− mice
Intraperitoneal injection
10 mg/kg
Daily injections for 24 days
PF-670462 significantly lengthened the period of behavioral rhythms in WT, Ck1εtau, and Ck1ε?/? mice, with dose-dependent effects.
Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15240-5.
Rats
Alcohol Deprivation Effect model
Intraperitoneal injection
0, 10, and 30 mg/kg
Every 12 hours, total of 5 injections
PF-670462 dose-dependently decreased and prevented the alcohol deprivation effect, with the higher dosage completely preventing the alcohol deprivation effect.
Neuropsychopharmacology. 2012 Aug;37(9):2121-31
Mice
DSS-induced ulcerative colitis model
Subcutaneous injection
50 mg/kg
Once daily, throughout the experiment
PF-670462 inhibited the deterioration of DSS-induced ulcerative colitis caused by UVB eye irradiation.
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