Effective drug delivery to the brain is critical for the treatment of glioblastoma (GBM), an aggressive and invasive primary brain tumor that has a dismal prognosis. Radiation therapy, the mainstay of brain tumor treatment, works by inducing DNA damage. Therefore, inhibiting DNA damage response (DDR) pathways can sensitize tumor cells to radiation and enhance cytotoxicity. AZD1390 is an inhibitor of ataxia-telangiectasia mutated kinase, a critical regulator of DDR. Our in vivo studies in the mouse indicate that delivery of AZD1390 to the central nervous system (CNS) is restricted due to active efflux by P-glycoprotein (P-gp). The free fraction of AZD1390 in brain and spinal cord were found to be low, thereby reducing the partitioning of free drug to these organs. Coadministration of an efflux inhibitor significantly increased CNS exposure of AZD1390. No differences were observed in distribution of AZD1390 within different anatomic regions of CNS, and the functional activity of P-gp and breast cancer resistance protein also remained the same across brain regions. In an intracranial GBM patient–derived xenograft model, AZD1390 accumulation was higher in the tumor core and rim compared with surrounding brain. Despite this heterogenous delivery within tumor-bearing brain, AZD1390 concentrations in normal brain, tumor rim, and tumor core were above in vitro effective radiosensitizing concentrations. These results indicate that despite being a substrate of efflux in the mouse brain, sufficient AZD1390 exposure is anticipated even in regions of normal brain.

中文翻译：

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共济失调毛细血管扩张突变激酶抑制剂 AZD1390 的中枢神经系统分布：对脑肿瘤治疗的影响

有效地将药物输送到大脑对于治疗胶质母细胞瘤（GBM）至关重要，胶质母细胞瘤是一种侵袭性、侵袭性的原发性脑肿瘤，预后不佳。放射治疗是脑肿瘤治疗的主要手段，通过诱导 DNA 损伤发挥作用。因此，抑制DNA损伤反应（DDR）途径可以使肿瘤细胞对辐射敏感并增强细胞毒性。AZD1390 是共济失调毛细血管扩张突变激酶的抑制剂，该激酶是 DDR 的关键调节因子。我们对小鼠的体内研究表明，由于 P-糖蛋白 (P-gp) 的主动外排，AZD1390 向中枢神经系统 (CNS) 的递送受到限制。发现大脑和脊髓中 AZD1390 的游离部分较低，从而减少了游离药物到这些器官的分配。外排抑制剂的共同给药显着增加了 AZD1390 的 CNS 暴露。AZD1390在中枢神经系统不同解剖区域内的分布没有观察到差异，P-gp和乳腺癌抗性蛋白的功能活性在不同脑区域也保持相同。在颅内 GBM 患者来源的异种移植模型中，与周围大脑相比，AZD1390 在肿瘤核心和边缘的积累较高。尽管在荷瘤脑内存在这种异质递送，但正常脑、肿瘤边缘和肿瘤核心中的 AZD1390 浓度高于体外有效放射增敏浓度。这些结果表明，尽管 AZD1390 是小鼠大脑中流出的底物，但即使在正常大脑区域中，预计也会有足够的 AZD1390 暴露。