D4476 is a dual inhibitor of both ALK5 with IC50 value of 94nM, and CK1 with IC50 values of 200nM and 300nM for CK1 and CK1δ from S. pombe, respectively[1][2]. D4476 inhibited TGF-β1-induced (FN) mRNA formation in A498 cells with IC50 value of 0.05μM and significantly reduced the TGF-β1-induced nuclear accumulation of Smad proteins with an IC50 value of 0.04 µM[1]. D4476 dose-dependently inhibited the phosphorylation of FOXO1a induced by insulin at Ser322 and Ser325 at concentration ranging in 25-150μM in H4IIE cells, but not the phosphorylation of Thr24, Ser256, Ser319 catalyzed by PKB, or the constitutively phosphorylated Ser329. Prior treatment with 150μM D4476 reduced the IGF-1 and serum-induced nuclear exclusion of FOXO1a to about 3 fold. This retarding of nuclear exclusion by D4476 may due to the acceleration of nuclear export[2].
作用机制
D4476 is an ATP-competitive inhibitor of CK1.
D4476 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Red Blood Cells
10 µM
To evaluate the effect of D4476 on GAL-induced eryptosis.
Int J Mol Sci. 2024 Nov 15;25(22):12267.
HEK293 cells
10 µM
1 day
Chemical inhibition of CK1 α by D4476 led to a drastic increase in LT protein levels compared to cells treated with dimethyl sulfoxide (DMSO). CHIR99021 treatment did not change LT levels, reinforcing that CK1 α is one of the main negative regulatory kinases of LT.
mBio. 2024 Aug 14;15(8):e0111724.
U2OS cells
10 µM
1 day
D4476 treatment greatly increased the interaction between CK1α and LT, indicating that CK1α kinase activity is required for LT degradation.
mBio. 2024 Aug 14;15(8):e0111724.
Hep3B cells
10 µM
48 hours
Pretreatment with D4476 effectively protected cells against TGF-β-induced apoptosis and reversed TGF-β-induced Bim up-regulation.
Protein Cell. 2015 Feb;6(2):127-38.
Mouse ovarian granulosa cells
50 µM
6 hours
To validate the regulatory role of CK1α in estrogen synthesis, results showed that D4476 treatment increased apoptosis in granulosa cells and reduced estrogen synthesis.
BMC Biol. 2024 Aug 26;22(1):176.
Lens epithelial cells
10 µM
Mechanistically, NAM enhanced the differentiation and transparency of regenerative lenses partly by inhibiting casein kinase 1A activity.
搜索
