Bioscience, Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
Oncology Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, United Kingdom.
Clin Cancer Res. 2024 Apr 1;30(7):1338-1351. doi: 10.1158/1078-0432.CCR-23-2094.
We evaluated the properties and activity of AZD9574, a blood-brain barrier (BBB) penetrant selective inhibitor of PARP1, and assessed its efficacy and safety alone and in combination with temozolomide (TMZ) in preclinical models.
AZD9574 was interrogated in vitro for selectivity, PARylation inhibition, PARP-DNA trapping, the ability to cross the BBB, and the potential to inhibit cancer cell proliferation. In vivo efficacy was determined using subcutaneous as well as intracranial mouse xenograft models. Mouse, rat, and monkey were used to assess AZD9574 BBB penetration and rat models were used to evaluate potential hematotoxicity for AZD9574 monotherapy and the TMZ combination.
AZD9574 demonstrated PARP1-selectivity in fluorescence anisotropy, PARylation, and PARP-DNA trapping assays and in vivo experiments demonstrated BBB penetration. AZD9574 showed potent single agent efficacy in preclinical models with homologous recombination repair deficiency in vitro and in vivo. In an O6-methylguanine-DNA methyltransferase (MGMT)-methylated orthotopic glioma model, AZD9574 in combination with TMZ was superior in extending the survival of tumor-bearing mice compared with TMZ alone.
The combination of three key features-PARP1 selectivity, PARP1 trapping profile, and high central nervous system penetration in a single molecule-supports the development of AZD9574 as the best-in-class PARP inhibitor for the treatment of primary and secondary brain tumors. As documented by in vitro and in vivo studies, AZD9574 shows robust anticancer efficacy as a single agent as well as in combination with TMZ. AZD9574 is currently in a phase I trial (NCT05417594). See related commentary by Lynce and Lin, p. 1217.
我们评估了 AZD9574 的特性和活性，AZD9574 是一种血脑屏障（BBB）穿透性的 PARP1 选择性抑制剂，评估了其单独使用和与替莫唑胺（TMZ）联合在临床前模型中的疗效和安全性。
在体外，AZD9574 的选择性、PAR 化抑制、PARP-DNA 捕获、穿过血脑屏障的能力以及抑制癌细胞增殖的能力进行了检测。使用皮下和颅内小鼠异种移植模型确定体内疗效。使用小鼠、大鼠和猴子来评估 AZD9574 的血脑屏障穿透性，并用大鼠模型来评估 AZD9574 单药治疗和 TMZ 联合治疗的潜在血液毒性。
AZD9574 在荧光各向异性、PAR 化、PARP-DNA 捕获测定以及体内实验中表现出 PARP1 的选择性，并且在体内实验中显示出 BBB 穿透性。AZD9574 在同源重组修复缺陷的体外和体内临床前模型中表现出强大的单药疗效。在 O6-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）-甲基化的原位胶质瘤模型中，与 TMZ 单药治疗相比，AZD9574 与 TMZ 联合治疗可延长荷瘤小鼠的生存时间。
单一分子中 PARP1 选择性、PARP1 捕获谱和中枢神经系统高穿透性这三个关键特征的结合，支持将 AZD9574 开发为治疗原发性和继发性脑肿瘤的同类最佳 PARP 抑制剂。如体外和体内研究所述，AZD9574 作为单一药物以及与 TMZ 联合使用均具有强大的抗癌疗效。AZD9574 目前正在进行 I 期临床试验（NCT05417594）。请参阅 Lynce 和 Lin 的相关评论，第 1217 页。
