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NU7441 (also called KU-57788) is a highly potent, selective and ATP-competitive inhibitor of DNA-PK (DNA-dependent protein kinase) with IC50 of 14 nM, has anticancer activity. Additionally, it inhibits PI3K in cell-free assays with an IC50 value of 5 M. At a concentration of 100 μM, the DNA-PK-related enzymes ATM and ATR were not inhibited by NU7441. With IC50 values for mTOR and PI3K that were 1.7 and 5 M, respectively—roughly 100 times higher than the IC50 value for DNA-PK—NU7441 demonstrated inhibition activities. In vitro, NU7441 made HeLa cells more sensitive to ionizing radiation, with dose modification factors of 2.5 at 10% survival being seen at 0.5 microM.
Physicochemical Properties
| Molecular Formula | C25H19NO3S | |
| Molecular Weight | 413.49 | |
| Exact Mass | 413.108 | |
| Elemental Analysis | C, 72.62; H, 4.63; N, 3.39; O, 11.61; S, 7.75 | |
| CAS # | 503468-95-9 | |
| Related CAS # |
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| PubChem CID | 11327430 | |
| Appearance | Off-white to beige solid powder | |
| Density | 1.4±0.1 g/cm3 | |
| Boiling Point | 646.9±55.0 °C at 760 mmHg | |
| Melting Point | 246.28° C | |
| Flash Point | 345.0±31.5 °C | |
| Vapour Pressure | 0.0±1.9 mmHg at 25°C | |
| Index of Refraction | 1.732 | |
| LogP | 5.98 | |
| Hydrogen Bond Donor Count | 0 | |
| Hydrogen Bond Acceptor Count | 5 | |
| Rotatable Bond Count | 2 | |
| Heavy Atom Count | 30 | |
| Complexity | 690 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | S1C2=C([H])C([H])=C([H])C([H])=C2C2C([H])=C([H])C([H])=C(C1=2)C1=C([H])C([H])=C([H])C2C(C([H])=C(N3C([H])([H])C([H])([H])OC([H])([H])C3([H])[H])OC1=2)=O |
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| InChi Key | JAMULYFATHSZJM-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C25H19NO3S/c27-21-15-23(26-11-13-28-14-12-26)29-24-17(6-3-9-20(21)24)19-8-4-7-18-16-5-1-2-10-22(16)30-25(18)19/h1-10,15H,11-14H2 | |
| Chemical Name | 8-dibenzothiophen-4-yl-2-morpholin-4-ylchromen-4-one | |
| Synonyms | NU7441; NU 7441; NU-7441; KU 57788; KU57788; KU-57788 | |
| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | DNA-PK (IC50 = 14 nM); mTOR (IC50 = 1.7 μM); PI3K (IC50 = 5.0 μM); CRISPR/Cas9 |
| ln Vitro | NU7441 increases the persistence of γH2AX foci after ionizing radiation–induced or etoposide-induced DNA damage. In both SW620 and LoVo cells, NU7441 (0.5 μM or 1 μM) significantly increases G2-M accumulation brought on by ionizing radiation, etoposide, and doxorubicin. [2] In addition to making DNA double-strand breaks more persistent, NU7441 also slightly reduces the activity of homologous recombination in DNA-PK-sufficient M059-Fus-1 and DNA-PK-sufficient M059 J human tumor cells.[3] In cells that express polymerase as well as those that lack it, NU7441 inhibits UV-induced RPA p34 hyperphosphorylation in a dose-dependent manner. [4] In chronic lymphocytic leukemia cells, NU7441 causes fludarabine-induced H2AX foci to accumulate and, in turn, reduces fludarabine-induced cell death. [5] In addition, DNA-PKcs autophosphorylation and repair brought on by mitoxantrone in cells of chronic lymphocytic leukemia are inhibited by NU7441.[6] In the aftermath of Cas9-mediated DNA cleavage, it decreases the frequency of NHEJ while increasing the rate of HDR[7]. |
| ln Vivo | In mice bearing SW620 xenografts, administration of NU7441 intraperitoneally at a dose of 10 mg/kg for at least 4 hours demonstrates nontoxicity and increases etoposide-induced tumor growth delay by a factor of two.[2] |
| Enzyme Assay | NU7441 (also called KU-57788) is a highly potent, selective and ATP-competitive DNA-PK inhibitor with IC50 of 14 nM. It also inhibits PI3K with IC50 value of 5 μM in cell-free assays. |
| Cell Assay | HepG2 cells (4000 per well) are cultured in a 96-well plate for 24 h. The culture media are then supplemented with concentrations of 0.1 µM, 1 µM, 5 µM, and 10 µM of KU-57788 once the cells have finished adhering. 10% CCK-8 solution is added to the culture media after KU-57788 treatment has been going on for 12 hours.Incubation is then continued for another 2 hours. A spectrometer is used to calculate the OD450 values, and the results are then analyzed to calculate the rate of cell growth. |
| Animal Protocol |
Female rude mice bearing SW620 xenografts 10 mg/kg Intraperitoneally administrated |
| References |
[1]. Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries. Bioorg Med Chem Lett. 2004 Dec 20;14(24):6083-7. [2]. NU7441 Enhances the Radiosensitivity of Liver Cancer Cells. Cell Physiol Biochem. 2016;38(5):1897-905. [3]. Discovery of potent chromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK) using a small-molecule library approach. J Med Chem. 2005 Dec 1;48(24):7829-46. [4]. The acetyl-lysine binding site of bromodomain-containing protein 4 (BRD4) interacts with diverse kinase inhibitors. ACS Chem Biol. 2014 Feb 25. [5]. Pharmacological inhibition of DNA-PK stimulates Cas9-mediated genome editing. Genome Med. 2015 Aug 27;7:93. |
| Additional Infomation | 8-(4-dibenzothiophenyl)-2-(4-morpholinyl)-1-benzopyran-4-one is a member of dibenzothiophenes. |
Solubility Data
| Solubility (In Vitro) |
DMSO: ~4 mg/mL warming (~9.7 mM) Water: <1 mg/mL (slightly soluble or insoluble) Ethanol: <1 mg/mL (slightly soluble or insoluble) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.43 mg/mL (3.46 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 14.3 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. AO:AO 4%DMSO+30%PEG 300+5%Tween 80+ddH2O: 1.0mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4184 mL | 12.0922 mL | 24.1844 mL | |
| 5 mM | 0.4837 mL | 2.4184 mL | 4.8369 mL | |
| 10 mM | 0.2418 mL | 1.2092 mL | 2.4184 mL |