in vitro: VE-822, a close analog of VE-821, has increased potency against ATR retaining the excellent ATR selectivity pro?le. Furthermore, VE-822 has absorption, distribution, metabolism and excretion properties that support in vivo studies. Particularly, VE-822 has 4100-fold cellular ATR-selectivity over the closely related phosphatidylinositol 3-kinase-related kinases ATM/DNA-PK. VE-822 increased XRT-induced residual gH2AX and 53BP1 foci compared with XRT (Figures 3a and b). VE-822 pretreatment decreased Rad51 foci after XRT. VE-822 alone had no effect on gH2AX, 53BP1 or Rad51 foci. VE-822 alone increased the G1-phase-fraction. XRT enriched G2/M-phase-fraction, and this was abrogated by co-treatment with VE-822. By contrast, gemcitabine-induced S-phase arrest that was not affected by VE-822.

in vivo: Intermittent VE-822 dosing (days 0, 2 and 4) at three different doses (15, 30 and 60 mg/kg) was tested for radiosensitisation, and the time for tumors to grow to 400 mm3 (TV400) was analyzed. A clear dose-dependent radiosensitisation response to VE-822 was observed, with 60 mg/kg the most efficacious dose. No weight loss was observed in any of the mice.