4-(4-(2,3-DIHYDROBENZO[1,4]DIOXIN-6-YL)-5-PYRIDIN-2-YL-1H-IMIDAZOL-2-YL)BENZAMIDE

Description

D 4476 is a cell-permeant inhibitor of casein kinase 1 (CK1; IC₅₀ = 200 nM from S. pombe, 300 nM for CK1δ). It is a less effective inhibitor of PKD1 (IC₅₀ = 9.1 μM) and p38α MAPK (IC₅₀ = 5.8 μM), and only weakly affects the activities of a panel of kinases tested. D 4476 blocks CK1-mediated phosphorylation of FOXO1a, RhoB, and p53. As an inhibitor of ALK5, D 4476 prevents Smad3 activation and suppresses TGF-β1-induced gene expression without cytotoxicity in A498 cells.

Uses

D4476 has been used as a casein kinase I inhibitor (CKI) in various experiments.

Uses

4-[4-(2,3-Dihydro-1,4-benzodioxin-6-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]-benzamide is a novel CK1 inhibitor that potently inhibits CK1 with an IC50 value of 78 nM.

Definition

ChEBI: 4-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]benzamide is a member of imidazoles.

Biological Activity

Selective inhibitor of casein kinase 1 (CK1) and TGF- β type-I receptor (ALK5) that displays > 20-fold selectivity over SAPK2/p38 and a much greater selectivity over all other protein kinases tested. Suppresses site-specific phosphorylation and nuclear exclusion of FOXO1a.

Biochem/physiol Actions

D4476 may prevent or enhance apoptosis. It triggers tumor suppressor p53 and impairs transcription factor E2F-1.

storage

+4°C

References

1. g. rena, j. bain, m. elliott and p. cohen, embo rep 2004, 5, 60-65. 2. v. tillement, i. lajoie-mazenc, a. casanova, c. froment, m. penary, d. tovar, r. marquez, b. monsarrat, g. favre and a. pradines, exp cell res 2008, 314, 2811-2821. 3. a. s. huart, n. j. maclaine, d. w. meek and t. r. hupp, j biol chem 2009, 284, 32384-32394.