D4476 is a relatively specific and cell-permeant inhibitor of CK1 and ALK5 with respective IC50 values of 0.3 and 0.5 μM at 0.1 mM ATP in vitro.[1]
CK1 (casein kinase 1) phosphorylates serine residues that are located close to another phosphoserine in multisite phosphorylation domains (MPDs). D4476 may be an ATP-competitive inhibitor of CK1. It weakly inhibits SAPK2a/p38 and does not inhibit PKB or SGK. In H4IIE cells, the site-specific phosphorylation (Ser322 and Ser325) of FOXO1a was inhibited at 50 and 125 μM, which reduced the initial rate of nuclear exclusion[1]. In Hela cells, the phosphorylation(Ser185) of RhoB caused by CK1 was inhibited by D4476 at 50 μM then the RhoB-dependent actin fiber formation was subsequently activated[2]. D4476 treatment has been observed to result in a partial p53-dependent growth arrest in HCT116 cells.[3]
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.