D 4476 is a cell-permeant inhibitor of casein kinase 1 (CK1; IC50 = 200 nM from S. pombe,1 300 nM for CK1δ2). 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.2 D 4476 blocks CK1-mediated phosphorylation of FOXO1a,1 RhoB,3 and p53.4 As an inhibitor of ALK5, D 4476 prevents Smad3 activation and suppresses TGF-β1-induced gene expression without cytotoxicity in A498 cells.5
1
Rena, G., Bain, J., Elliot, M., et al. D4476, a cell-permeant inhibitor of CK1, suppresses the site-specific phosphorylation and nuclear exclusion of FOXO1a. EMBO Rep5(1)60-65(2004).
2
Bain, J., Plater, L., Elliot, M., et al. The selectivity of protein kinase inhibitors: A further update. Biochem J408297-315(2007).
3
Tillement, V., Lajoie-Mazenc, I., Casanova, A., et al. Phosphorylation of RhoB by CK1 impedes actin stress fiber organization and epidermal growth factor receptor stabilization. Exp Cell Res3142811-2821(2008).
4
MacLaine, N.J., Øster, B., Bundgaard, B., et al. A central role for CK1 in catalyzing phosphorylation of the p53 transactivation domain at serine 20 after HHV-6B viral infection. J Biol Chem283(42)28563-28573(2008).
5
Callahan, J.F., Burgess, J.L., Fornwald, J.A., et al. Identification of novel inhibitors of the transforming growth factor b1 (TGF-b1) type 1 receptor (ALK5). J Med Chem45(5)999-1001(2002).
MacLaine, N.J., Øster, B., Bundgaard, B., et al. A central role for CK1 in catalyzing phosphorylation of the p53 transactivation domain at serine 20 after HHV-6B viral infection. J Biol Chem283(42)28563-28573(2008).
Callahan, J.F., Burgess, J.L., Fornwald, J.A., et al. Identification of novel inhibitors of the transforming growth factor b1 (TGF-b1) type 1 receptor (ALK5). J Med Chem45(5)999-1001(2002).
Rena, G., Bain, J., Elliot, M., et al. D4476, a cell-permeant inhibitor of CK1, suppresses the site-specific phosphorylation and nuclear exclusion of FOXO1a. EMBO Rep5(1)60-65(2004).
Bain, J., Plater, L., Elliot, M., et al. The selectivity of protein kinase inhibitors: A further update. Biochem J408297-315(2007).
Tillement, V., Lajoie-Mazenc, I., Casanova, A., et al. Phosphorylation of RhoB by CK1 impedes actin stress fiber organization and epidermal growth factor receptor stabilization. Exp Cell Res3142811-2821(2008).