D4476
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.
| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 398.41 |
| Cas No. | 301836-43-1 |
| Formula | C23H18N4O3 |
| Synonyms | Casein Kinase I Inhibitor;D 4476;D-4476 |
| Solubility | insoluble in H2O; ≥19.9 mg/mL in DMSO; ≥41.5 mg/mL in EtOH with gentle warming and ultrasonic |
| Chemical Name | 4-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide |
| SDF | Download SDF |
| Canonical SMILES | C1COC2=C(O1)C=CC(=C2)C3=C(NC(=N3)C4=CC=C(C=C4)C(=O)N)C5=CC=CC=N5 |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment [1,2]: | |
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Cell lines |
H4IIE, Hela and HCT116 cell lines |
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Preparation method |
The solubility of this compound in DMSO is >19.9 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
H4IIE: 0-150 μM for 1 h; Hela: 50 μM; HCT116: 5-40 μM for 48 h |
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Applications |
In H4IIE hepatoma cells, D4476 specifically inhibited the phosphorylation of endogenous forkhead box transcription factor O1a (FOXO1a) on Ser322 and Ser325 within its MPD, without affecting the phosphorylation of other sites. It was also found that although the treatment of in HCT116 cells with D4476 led to a partial p53-dependent growth arrest, the induction of p53-independent apoptosis by D4476 suggested a critical role for the MDM2-CK1 complex in maintaining E2F-1 anti-apoptotic signaling. |
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References: [1] Rena G, et al. D4476, a cell-permeant inhibitor of CK1, suppresses the site-specific phosphorylation and nuclear exclusion of FOXO1a. EMBO Rep. 2004 Jan;5(1):60-5. [2] Huart AS, MacLaine NJ, Meek DW, Hupp TR.CK1alpha plays a central role in mediating MDM2 control of p53 and E2F-1 protein stability. J Biol Chem. 2009 Nov 20;284(47):32384-94. |
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