PF-4800567 is a selective, ATP competitive casein kinase 1ε inhibitor with IC50 values of 32 and 711 nM for CK1ε and CK1δ respectively. 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. PF-4800567 displays 22-fold greater potency towards CK1ε than CK1δ. PF-4800567 completely blocks CK1epsilon-mediated PER3 nuclear localization and PER2 degradation.
|Source||Oncogene (2011). Figure 5. PF-4800567|
|Method||cell proliferation assay|
|Cell Lines||HEK293 and HT1080 cell|
|Incubation Time||24 h|
|Results||We confirmed that PF480 selectively inhibited CK1ɛ using the in vivo autophosphorylation assay. PF480 was less effective than PF670 at inhibition of Wnt/β-catenin signaling|
|Cell lines||COS-7 cells|
|Preparation method||Nuclear Translocation.
CK1ϵ- and CK1δ-dependent PER3 nuclear translocation was run as described previously for CK1ϵ (Badura et al., 2007), with alterations as indicated below. CK1δ-dependent PER3 nuclear translocation was performed with human full-length CKIδ-pcDNA4/HisA cotransfected into COS-7 cells with the GFP-tagged murine PER3. The sensitivity of the assay was increased by incorporating an anti-GFP antibody-staining step. After the plates were fixed with 4% paraformaldehyde and washed in PBS, cells were blocked and permeabilized in PBS with 4% goat serum and 0.1% Triton X-100 for 1 h at room temperature. Blocking buffer was then replaced with a polyclonal anti-GFP antibody (Invitrogen), diluted 1:1000 in blocking buffer, and incubated for 2 h. After three washes in PBS, goat anti-rabbit Alexa Fluor 488 secondary antibody (Invitrogen), diluted 1:1000 in Hoechst staining solution, was added and incubated for 1 h before three final washes in PBS.
|Concentrations||0, 0.01, 0.1, 1, 10μM|
|Incubation time||1~2 hr|
|Animal models||C57BL/6J mice|
|Formulation||20% hydroxypropyl β-cyclodextrin|
|Dosages||100 mg/kg daily for 3 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥30 mg/mL|
Selective inhibition of casein kinase 1 epsilon minimally alters circadian clock period.
Walton KM, et al. J Pharmacol Exp Ther. 2009 Aug;330(2):430-9. PMID: 19458106.
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TA-01 potently inhibits CK1ε, CK1δ,and p38α (IC50values are 6.4, 6.8, and 6.7 nM respectively).
TBB(NSC 231634) is a highly selective, ATP/GTP-competitive inhibitor of casein kinase-2 (CK2)with IC50s of 0.9 and 1.6 μM for rat liver and human recombinant CK2 respectively).
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