A majority of cancer patients receive radiation therapy as part of their treatment regimens whether using external beam therapy or locally-delivered radioisotopes. While often effective, some tumors are inadequately controlled with radiation and radiation therapy has significant short-term and long-term toxicities for cancer survivors. Insights into molecular mechanisms involved in cellular responses to DNA breaks introduced by radiation or other cancer therapies have been gained in recent years and approaches to manipulate these responses to enhance tumor cell killing or reduce normal tissue toxicity are of great interest. Here, we report the identification and initial characterization of XRD-0394, a potent and specific dual inhibitor of two DNA damage-response kinases, ATM and DNA-PKcs. This orally bioavailable molecule demonstrates significantly enhanced tumor cell kill in the setting of therapeutic ionizing irradiation in vitro and in vivo. XRD-0394 also potentiates the effectiveness of topoisomerase I inhibitors in vitro. Additionally, in cells lacking BRCA1/2 XRD-0394 shows single agent activity and synergy in combination with PARP inhibitors. A Phase Ia clinical trial (NCT05002140) with XRD-0394 in combination with RT has completed. These results provide a rationale for future clinical trials with XRD-0394 in combination with RT, PARP inhibitors and targeted delivery of topoisomerase I inhibitors.

中文翻译：

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一种新型 ATM/DNA-PK 双重抑制剂 XRD-0394，可有效增强放射增敏作用并增强 PARP 和拓扑异构酶 I 抑制剂

大多数癌症患者接受放射治疗作为其治疗方案的一部分，无论是使用外部放射治疗还是局部放射同位素。虽然通常有效，但一些肿瘤无法通过放射治疗得到充分控制，并且放射治疗对癌症幸存者具有显着的短期和长期毒性。近年来，人们对辐射或其他癌症疗法引起的 DNA 断裂的细胞反应的分子机制有了深入的了解，操纵这些反应以增强肿瘤细胞杀伤或减少正常组织毒性的方法引起了人们的极大兴趣。在此，我们报告了 XRD-0394 的鉴定和初步表征，它是两种 DNA 损伤反应激酶（ATM 和 DNA-PKcs）的有效且特异性的双重抑制剂。这种口服生物可利用的分子在体外和体内电离治疗辐射的情况下显示出显着增强的肿瘤细胞杀伤力。 XRD-0394 还可以增强拓扑异构酶 I 抑制剂的体外有效性。此外，在缺乏 BRCA1/2 的细胞中，XRD-0394 显示出单药活性以及与 PARP 抑制剂组合的协同作用。 XRD-0394 与 RT 联合的 Ia 期临床试验 (NCT05002140) 已经完成。这些结果为 XRD-0394 与 RT、PARP 抑制剂和拓扑异构酶 I 抑制剂的靶向递送相结合的未来临床试验提供了理论依据。