NU7441 (KU-57788) is a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor with an IC50 of 13nM[1]. NU7441 also inhibits phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) with IC50 of 5.0 and 1.7μM, respectively[2]. NU7441 is an inhibitor of the non-homologous end joining (NHEJ) pathway[3].
In vitro, NU7441 (0.1-10μM) treatment of human hepatocellular carcinoma HepG2 cells for 72h dose- and time-dependently inhibited cell proliferation, reduced cellular pDNA-PKcs (S2056) protein expression, increased G2/M phase arrest of the cell cycle and induced apoptosis[4]. NU7441 (0.5-10µM) treatment of human oral squamous cell carcinoma cell lines (HSC2 and HSC2-R cells) for 0-48h significantly enhanced 6Gy X-ray irradiation-induced apoptosis and abolished colony formation in both cell lines[5].
In vivo, NU7441 (10mg/kg/day) was treated by intraperitoneal injection for 10 days in ovalbumin-induced asthmatic mice, which aggravated the degree of DNA damage in the mouse airways, but inhibited the infiltration of inflammatory cells and the level of inflammatory cytokines in the lungs[6]. NU7441 (5mg/kg) was treated by intratracheal administration in acute lung injury (ALI) mice, which significantly reduced pulmonary edema and reduced the production of inflammatory cytokines in bronchoalveolar lavage fluid (BALF)[7].
References:
[1] Hardcastle I R, Cockcroft X, Curtin N J, et al. Discovery of potent chromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK) using a small-molecule library approach[J]. Journal of medicinal chemistry, 2005, 48(24): 7829-7846.
[2] Ma C C, Li H, Wan R Z, et al. Developments of DNA-dependent protein kinase inhibitors as anticancer agents[J]. Mini Reviews in Medicinal Chemistry, 2014, 14(11): 884-895.
[3] Iglesias-Corral D, García-Valles P, Arroyo-Garrapucho N, et al. Chloroquine-induced DNA damage synergizes with DNA repair inhibitors causing cancer cell death[J]. Frontiers in Oncology, 2024, 14.
[4] Yang C, Wang Q, Liu X, et al. NU7441 enhances the radiosensitivity of liver cancer cells[J]. Cellular Physiology and Biochemistry, 2016, 38(5): 1897-1905.
[5] Ohuchi K, Saga R, Hasegawa K, et al. DNA PKcs phosphorylation specific inhibitor, NU7441, enhances the radiosensitivity of clinically relevant radioresistant oral squamous cell carcinoma cells[J]. Biomedical Reports, 2023, 18(4): 1-8.
[6] Wang Y, Lin J, Shu J, et al. Oxidative damage and DNA damage in lungs of an ovalbumin-induced asthmatic murine model[J]. Journal of Thoracic Disease, 2018, 10(8): 4819.
[7] Pyakurel K, Ghonim M, Ibba S, et al. DNA‐Dependent Protein Kinase Inhibition Prevents Manifestation of Acute Lung Injury in Mice, a Novel Target Associated with Th1 Type Disease[J]. The FASEB Journal, 2016, 30: 1202.4-1202.4.
NU7441 (KU-57788)是一种高效的选择性DNA依赖性蛋白激酶（DNA-PK）抑制剂，IC50为13nM[1]。NU7441还抑制磷脂酰肌醇3-激酶（PI3K）和哺乳动物雷帕霉素靶蛋白（mTOR），IC50分别为5.0和1.7μM[2]。NU7441是非同源性末端接合（NHEJ）通路抑制剂[3]。
在体外，NU7441（0.1-10µM）处理人肝癌HepG2细胞72h，剂量和时间依赖性地抑制了细胞增殖，降低了细胞pDNA-PKcs（S2056）蛋白表达，增加了细胞周期的G2/M期阻滞和诱导细胞凋亡[4]。NU7441（0.5-10µM）处理人口腔鳞状细胞癌细胞系（HSC2和HSC2-R细胞） 0-48h，显著增强了6Gy X射线照射诱导的细胞凋亡，消除了两种细胞系中的集落形成[5]。
在体内，NU7441（10mg/kg/day）通过腹腔注射治疗卵清蛋白诱导的哮喘小鼠10天，加重了小鼠气道的DNA损伤程度，但抑制了肺部炎症细胞的浸润和炎症细胞因子的水平[6]。NU7441（5mg/kg）通过气管内施用治疗急性肺损伤（ALI）小鼠，显著减少了小鼠的肺水肿，减少了支气管肺泡灌洗液（BALF）中炎症细胞因子的产生[7]。