VE-821

VE-821 is a novel ATR inhibitor. VE-821 was shown to inhibit ATR-mediated signalling in response to replication arrest induced by severe hypoxia. VE-821 inhibited radiation- and gemcitabine-induced phosphorylation of Chk1, confirming inhibition of ATR signaling. ATR inhibition by VE-821 led to inhibition of radiation-induced G 2/M arrest in cancer cells. Consistently, VE-821 significantly enhanced the sensitivity of PSN-1, MiaPaCa-2 and primary PancM pancreatic cancer cells to radiation and gemcitabine under both normoxic and hypoxic conditions. VE-821 induced DNA damage and consequently increased Ataxia Telangiectasia Mutated-mediated phosphorylation of H2AX and KAP1. Most importantly, VE-821 increased radiation-induced loss of viability in hypoxic conditions. Reduced cancer cell radiosurvival following treatment with VE-821 was also accompanied by increased DNA damage and inhibition of homologous recombination repair, as evidenced by persistence of γH2AX and 53BP1 foci and inhibition of Rad51 foci, respectively.