Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026

Br J Cancer. 2005 Oct 31;93(9):1011-8. doi: 10.1038/sj.bjc.6602823.


In this study we investigated the in vitro time dependence of radiosensitisation, pharmacokinetics and metabolism of NU7026, a novel inhibitor of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). At a dose of 10 muM, which is nontoxic to cells per se, a minimum NU7026 exposure of 4 h in combination with 3 Gy radiation is required for a significant radiosensitisation effect in CH1 human ovarian cancer cells. Following intravenous administration to mice at 5 mg kg(-1), NU7026 underwent rapid plasma clearance (0.108 l h(-1)) and this was largely attributed to extensive metabolism. Bioavailability following interperitoneal (i.p.) and p.o. administration at 20 mg kg(-1) was 20 and 15%, respectively. Investigation of NU7026 metabolism profiles in plasma and urine indicated that the compound undergoes multiple hydroxylations. A glucuronide conjugate of a bis-hydroxylated metabolite represented the major excretion product in urine. Identification of the major oxidation site as C-2 of the morpholine ring was confirmed by the fact that the plasma clearance of NU7107 (an analogue of NU7026 methylated at C-2 and C-6 of the morpholine ring) was four-fold slower than that of NU7026. The pharmacokinetic simulations performed predict that NU7026 will have to be administered four times per day at 100 mg kg(-1) i.p. in order to obtain the drug exposure required for radiosensitisation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Availability
  • Cell Proliferation / drug effects
  • Cell Proliferation / radiation effects
  • Chromones / metabolism*
  • Chromones / pharmacokinetics*
  • DNA-Activated Protein Kinase / antagonists & inhibitors*
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / metabolism*
  • Enzyme Inhibitors / pharmacokinetics*
  • Female
  • Gamma Rays
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Morpholines / metabolism*
  • Morpholines / pharmacokinetics*
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / radiotherapy
  • Radiation Tolerance
  • Tumor Stem Cell Assay


  • 2-(morpholin-4-yl)benzo(h)chromen-4-one
  • Chromones
  • Enzyme Inhibitors
  • Morpholines
  • DNA-Activated Protein Kinase