NU7026

NU7026 potentiates ionizing radiation induced cytotoxicity in a concentration-dependent manner in V3YAC and PARP-1+/+ cells. NU7026 completely abolishes potentially lethal damage recovery in growth-arrested cells. NU7026 inhibits DNA DSB repair by 56% in the V3YAC cell line. ^[1]

NU7026 (10 μM) potentiates the growth inhibitory effects of idarubicin, daunorubicin, doxorubicin, etoposide, mAMSA, and mitoxantrone with PF50 values ranging from approximately 19 for mAMSA to approximately 2 for idarubicin in K562 cells. NU7026 (10 μM) also potentiates the growth inhibitory effect of etoposide in this leukemia cell line with a PF50 value of 10.53. NU7026 (10 μM) enhances the etoposide-induced cell cycle G2 blockade in K562 cells. NU7026 potentiates topo II poisons involves inhibition of nonhomologous end joining and a G2/M checkpoint arrest. ^[2]

NU7026 (10 μM) exposure of 4 h in combination with 3 Gy radiation is required for a significant radiosensitisation effect in CH1 human ovarian cancer cells. ^[3]

NU7026 (< 10 μM) plus chlorambucil has synergistic cytotoxic activity at nontoxic doses of NU7026 in a CLL cell line (I83) and in primary CLL-lymphocytes. NU7026 (10 μM) increases chlorambucil-induced G(2)/M arrest in I83 cells. NU7026 (10 μM) enhances chlorambucil -induced γH2AX throughout the cell cycle in the I83 cell line. NU7026 (10 μM) Increases chlorambucil-Induced apoptosis in the I83 cell line. ^[4]

NU7026 (55 μM) results in a dramatic induction of telomere fusion in p53 null MEFs and significantly fewer telomere fusions in p53 and ligase IV double null MEFs. ^[5]

NU7026 (20mg/kg, i.v.) undergoes rapid plasma clearance (0.108/hour) in mice and this is largely attributed to extensive metabolism. Bioavailability following interperitoneal (i.p.) and p.o. administration of NU7026 at dose of 20 mg/kg is 20 and 15%, respectively. ^[3]

• Recombinant kinase assay

  Mammalian DNA-PK (500 ng/μL) is isolated from HeLa cell nuclear extract after chromatography using Q-Sepharose, S-Sepharose, and Heparin agarose. DNA-PK (250 ng) activity is measured at 30℃, in a final volume of 40 μL, in buffer containing 25 mM HEPES (pH 7.4), 12.5 mM MgCl₂, 50 mM KCl, 1 mM DTT, 10% v/v Glycerol, 0.1% w/v NP-40, and 1 mg of the substrate GST-p53N66 in polypropylene 96-well plates. To the assay mix, varying concentrations of NU7026 (in DMSO at a final concentration of 1% v/v) are added. After 10 min of incubation, ATP is added to give a final concentration of 50 μM, along with a 30-mer double-stranded DNA oligonucleotide (final concentration of 0.5 ng/mL), to initiate the reaction. After 1 hour with shaking, 150 μL of PBS are added to the reaction, and 5 μL are then transferred to a 96-well opaque white plate containing 45 μl of PBS per well, where the GSTp53N66 substrate is allowed to bind to the wells for 1 hour. The IC50s for the compounds in all of the enzymes assays are derived from sigmoidal plots using the graphic package Prism, in which the enzyme activity in the varying concentration of compounds is plotted against the concentration of compound.

• Cell lines

  A549 cells

• Concentrations

  10 μM

• Incubation Time

  3 h

• Method

  Cells were treated with indicated concentration of drug for 3 h.

• Animal Models

  Female BALB/c mice

• Dosages

  25 mg/kg

• Administration

  intraperitoneal injection or orally