Background:

VE-822 is an ATR inhibitor with an IC50 value of 0.019 μM. It is a close analog of VE-821 with a marked increase in potency against ATR.
Radiation (XRT) and chemotherapy induce chromosomal DNA lesions resulting in activation of the ataxia telangiectasiamutated (ATM) and ATM-Rad3-related (ATR) protein kinases in response to double-strand DNA breaks (DSBs) and replication stress, respectively. Defects in the DNA damage response (DDR) such as ATM and p53 deletion/mutation are common in human tumors and occur in up to 70% of patients with PDAC. They might lead to a differential response in DNA repair signaling between normal and tumor cells that could be exploited to increase killing of Radiation (XRT) and chemotherapy induce chromosomal DNA lesions.
In irradiated cancer cells, VE-822 decreased checkpoints of cell-cycle, decreased homologous recombination and increased persistent DNA damage. VE-822 decreased survival of pancreatic cancer cells but not normal cells in response to XRT or gemcitabine. VE-822 markedly prolonged growth delay of pancreatic cancer xenografts after XRT and gemcitabine-based chemoradiation without augmenting normal cell or tissue toxicity.
Reference:
1.Fokas E, Prevo R, Pollard JR et al. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis. 2012 Dec 6;3:e441.