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NU7441_Molecular_structure_CAS_503468-95-9)
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NU7441

Catalog No. S2638 Name Selleck Chemicals
CAS Number 503468-95-9 Website http://www.selleckchem.com
M. F. C25H19NO3S Telephone (877) 796-6397
M. W. 413.48826 Fax (832) 582-8590
Purity Email sales@selleckchem.com
Storage -20°C Chembase ID: 73213

SYNONYMS

IUPAC name
2-(morpholin-4-yl)-8-{8-thiatricyclo[7.4.0.0^{2,7}]trideca-1(13),2,4,6,9,11-hexaen-6-yl}-4H-chromen-4-one
IUPAC Traditional name
2-(morpholin-4-yl)-8-{8-thiatricyclo[7.4.0.0^{2,7}]trideca-1(13),2,4,6,9,11-hexaen-6-yl}chromen-4-one
Synonyms
KU-57788

DATABASE IDS

CAS Number 503468-95-9

PROPERTIES

Target ATM / DNA-PK / mTOR / PI3K
Salt Data Free Base
Storage Condition -20°C

DETAILS

Description (English)
Research Area
Description cancer
Biological Activity
Description NU7441 is a highly potent and selective DNA-PK inhibitor with IC50 of 14 nM.
Targets DNA-PK
IC50 14 nM [1]
In Vitro NU7441 increases the persistence of γH2AX foci after ionizing radiation–induced or etoposide-induced DNA damage. NU7441 (0.5 μM or 1 μM) appreciably increases G2-M accumulation induced by ionizing radiation, etoposide, and doxorubicin in both SW620 and LoVo cells. [2] NU7441 causes persistence of doxorubicin- and ionising radiation-induced DNA double-strand break and also slightly decreases homologous recombination activity DNA-PK-proficient M059-Fus-1 and DNA-PK-deficient M059 J human tumour cells. [3] NU7441 inhibits UV-induced RPA p34 hyperphosphorylation in a dose-dependent manner both in cells lacking and cells expressing polymerase η. [4] NU7441 increases levels of fludarabine-induced γH2AX foci and correspondingly decreased fludarabine-induced cell death in chronic lymphocytic leukemia cells. [5] NU7441 also inhibits mitoxantrone-induced DNA-PKcs autophosphorylation and repair in chronic lymphocytic leukemia cells. [6]
In Vivo NU7441 intraperitoneally administrated at dose of 10 mg/kg maintains for at least 4 hours shows nontoxic and increases etoposide-induced tumor growth delay 2-fold in mice bearing SW620 xenografts. [2]
Clinical Trials
Features
Combination Therapy
Description NU7441 increases the cytotoxicity of ionizing radiation and etoposide in W620, LoVo, and V3-YAC cells but not in V3 cells due to DNA-PK inhibition. [2]
Protocol
Cell Assay [2]
Cell Lines SW620, LoVo, V3-YAC and V3 cells
Concentrations 0.5 μM or 1 μM
Incubation Time 17 hours
Methods The effect of NU7441 on cellular survival following exposure to etoposide, doxorubicin, and ionizing radiation is measured in SW620, LoVo, V3, and V3-YAC cells by clonogenic assays. Briefly, growing cells in six-well plates or 6-cm dishes are exposed to etoposide or doxorubicin with or without NU7441 (0.5 or 1.0 μM) for 16 hours. For radiosensitization studies, NU7441 is added to the cells 1 hour before irradiation. V3 and V3-YAC cells are exposed to γ-irradiation (3.1 Gy/min 137Cesium). SW620 and LoVo are exposed to X-irradiation (2.9 Gy/min at 230 kV, 10 mA) due to the equipment available. After irradiation, the cells are incubated with or without NU7441 for a further 16 hours. Cells are then harvested by trypsinization, counted, and seeded into 10-cm diameter Petri dishes at densities varying from 100 to 105 per dish in drug-free medium for colony formation. Colonies are stained with crystal violet after 10 to 14 days and counted with an automated colony counter. The survival reduction factor (SRF) is calculated as the surviving fraction of cells in the absence of NU7441 divided by the surviving fraction of cells in the presence of NU7441 for any given dose or concentration of cytotoxic agent. The dose modification ratio (DMR90) is calculated as the concentration/dose of cytotoxic agent required to kill 90% of the cells in the absence of NU7441 divided by the concentration/dose of cytotoxic agent required to kill 90% of the cells in the presence of NU7441.
Animal Study [2]
Animal Models Female rude mice bearing SW620 xenografts
Formulation Sterile 0.9% sodium chloride solution
Doses 10 mg/kg
Administration Intraperitoneally administrated
References
[1] Leahy JJ, et al. Bioorg Med Chem Lett, 2004, 14(24), 6083-6087.
[2] Zhao Y, et al. Cancer Res, 2006 , 66(10), 5354-5362.
[3] Tavecchio M, et al. Cancer Chemother Pharmacol, 2012, 69(1), 155-164.
[4] Cruet-Hennequart S, et al. DNA Repair (Amst), 2006, 5(4), 491-504.
[5] Willmore E, et al. Clin Cancer Res, 2008, 14(12), 3984-3992.
[6] Elliott SL, et al. Br J Haematol, 2011, 152(1), 61-71.