NU7441

NU7441 (KU 57788) is a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor with IC50 values of 14, 1700, 5000, >100000 and >100000 nM for DNA-PK, mTOR, PI 3-K, ATM and ATR respectively. NU7441 strongly inhibited DNA-PK in cell lines (IC(50) = 0.3 μM) but only weakly inhibited PI3 K (IC(50) = 7 μM). The only available anti-phospho-DNA-PK antibody also recognised some phosphoprotein targets of ATM. NU7441 (KU 57788) caused doxorubicin- and IR-induced DNA DSBs (measured by γ-H2AX foci) to persist and also slightly decreased homologous recombination activity, as assessed by Rad51 foci. Chemo- and radio-potentiation were induced by NU7441 in M059-Fus-1, but not in DNA-PK-deficient M059 J cells. DNA-PK was highly expressed in a chronic lymphocytic leukaemia sample but undetectable in resting normal human lymphocytes, although it could be induced by PHA-P treatment. In K652 cells, DNA-PK expression was not related to cell cycle phase. NU7441 increased etoposide-induced tumor growth delay 2-fold without exacerbating etoposide toxicity to unacceptable levels. In conclusion, NU7441 (KU 57788) shows sufficient proof of principle through in vitro and in vivo chemosensitization and radiosensitization to justify further development of DNA-PK inhibitors for clinical use.