NU7441 (KU-57788 (NU7441)) is a highly effective and specific DNA-PK inhibitor (IC50: 14 nM).

DNA-PK:13 nM (cell free)

当KU-57788（NU7441）的浓度达到0.3 μM时，对正常细胞和肿瘤细胞均无毒性，但可以显著增加肿瘤细胞对X射线和碳离子的敏感性。这一浓度似乎不会抑制DNA DSB修复，但能显著诱导G2/M期阻滞[1]。在引入Cas9/sgGFP编辑系统和ΔGFP修复模板之后向细胞中添加NU7441，可以导致NHEJ事件大约减少40%，同时HDR的激活约增加两倍。这种效应是剂量依赖的，NU7441的最大效应约在2.0 μM时达到峰值[2]。NU7441降低了HepG2培养细胞中的CCK-8计数，并进一步增强了对HepG2细胞的60Co γ射线损伤，这通过降低DNA-PKcs (S2056) 蛋白表达、增加γ射线损伤来体现[3]。即使在UV辐射和抑制剂处理后，RPA p34仍定位于焦点中，但使用NU7441处理细胞可消除对高磷酸化RPA p34的染色[4]。

在对照组小鼠中，肿瘤体积在中位数5.6天时达到其初始体积的四倍(RTV4)。单独使用etoposide phosphate治疗可延长肿瘤生长2.7天，而联合使用NU7441后，肿瘤生长延迟时间延长至5.4天[5]。

Cells were irradiated with 290 MeV/n carbon ions (LET: 50 keV/μm) at the Heavy Ion Medical Accelerator in Chiba. The dose rate for carbon ions was 1 Gy/min. X‐ray irradiation was performed using a TITAN‐320 (200 kV, 20 mA) at a dose rate of 1 Gy/min. NU7441 was dissolved in DMSO and stored at ?20°C in a freezer. Cells were pretreated with NU7441 1 h before irradiation, and the drug was kept throughout the experiment [1].

All in vivo experiments were reviewed and approved by the relevant institutional animal welfare committees and done according to national law. We determined the plasma pharmacokinetics after administering NU7441 i.v. at 5 mg/kg in 10% DMSO/10% cyclodextrin in saline or i.p. or orally at 10 mg/kg (dissolved at 1 mg/mL in 40% PEG400/saline) to female BALB/c mice. These were the maximum administrable doses by the route used due to the limit of solubility of NU7441. Mice were killed at intervals up to 360 minutes after NU7441 administration; blood was taken and immediately centrifuged, and the plasma fraction was removed and stored at ?20°C [5].