The ataxia telangiectasia-mutated and Rad3-related protein (ATR) plays a crucial role in regulating the cellular DNA-damage response (DDR), making it a promising target for antitumor drug development through synthetic lethality. In this study, we present the discovery and detailed characterization of AD1058, a highly potent and selective ATR inhibitor, with good preclinical pharmacokinetic profiles. AD1058 exhibits superior efficacy in inhibiting cell proliferation, disrupting the cell cycle, and inducing apoptosis compared to AZD6738. AD1058 displays potent antitumor effects as a single agent or in combination with clinically approved tumor therapies such as PARP inhibitors, ionizing radiotherapy, or chemotherapy in vivo. Considering its enhanced ability to permeate the blood–brain barrier, AD1058 is a promising clinical candidate for the treatment of brain metastases and leptomeningeal metastases in solid tumors. Additionally, among reported ATR inhibitors, AD1058 features the shortest synthesis route and the highest efficiency to date.

中文翻译：

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发现临床前候选药物 AD1058 作为一种高效、选择性、脑渗透性 ATR 抑制剂，用于治疗晚期恶性肿瘤


共济失调毛细血管扩张突变和 Rad3 相关蛋白 (ATR) 在调节细胞 DNA 损伤反应 (DDR) 中发挥着至关重要的作用，使其成为通过合成致死性开发抗肿瘤药物的有前景的靶点。在这项研究中，我们介绍了 AD1058 的发现和详细表征，AD1058 是一种高效、选择性的 ATR 抑制剂，具有良好的临床前药代动力学特征。与 AZD6738 相比，AD1058 在抑制细胞增殖、破坏细胞周期和诱导细胞凋亡方面表现出卓越的功效。 AD1058 作为单一药物或与临床批准的肿瘤疗法（如 PARP 抑制剂、电离放疗或体内化疗）联合使用，显示出有效的抗肿瘤作用。考虑到其透过血脑屏障的能力增强，AD1058是治疗实体瘤脑转移和软脑膜转移的有前途的临床候选药物。此外，在已报道的ATR抑制剂中，AD1058具有迄今为止合成路线最短、效率最高的特点。