XRD-0394 (XRD0394) is a potent, specific, orally bioavailable dual inhibitor of DNA damage-response kinases ATM and DNA-PK with IC50 of 0.39 and 0.89 nM, respectively.
XRD-0394 is >100-fold selective for ATM and DNA-PK versus mTOR, PI3Kβ, ATR and SMG-1 and > 40-fold selective versus PI3Kγ and PI3Kδ, and 14-fold selective versus PI3Kα.
XRD-0394 inhibits phosphorylation by ATM and DNA-PK kinases, but not structurally related kinases, in human tumor cell.
XRD-0394 shows both significantly greater radiosensitization and less cellular toxicity in the absence of IR when compared to a specific ATR inhibitor, RP3500.
XRD-0394 also potentiates the effectiveness of topoisomerase I inhibitors in vitro.
XRD-0394 shows single agent activity and synergy in combination with PARP inhibitors in cells lacking BRCA1/2.
