靶向治疗仍然是抗癌药物开发的未来，因为目前的治疗缺乏特异性，会导致健康正常组织受损。 ATR 抑制剂最近表现出良好的临床潜力，目前正在临床中进行评估。然而，尽管人们对这些抑制剂的临床成功相当乐观，但相关正常组织毒性的报告仍然令人担忧，并可能损害其效用。 ICT10336 是一种新开发的 ATR 抑制剂 AZD6738 的缺氧反应性前药，它在体外缺氧条件下会被缺氧激活并特异性释放 AZD6738。 AZD6738 的缺氧选择性释放抑制了 ATR 激活（T1989 和 S428 磷酸化），随后消除了 HIF1a 介导的缺氧癌细胞适应，从而在 2D 和 3D 癌症模型中选择性诱导细胞死亡。重要的是，在正常组织中，ICT10336 被证明代谢稳定，并且对正常细胞的毒性低于其活性母体 AZD6738。此外，与AZD6738相比，ICT10336在3D肿瘤模型中表现出优越且高效的多细胞穿透能力，并选择性地根除缺氧核心的细胞。总之，临床前数据证明了一种肿瘤靶向递送 ATR 抑制剂的新策略，具有提高治疗指数的巨大潜力。© 2024 作者。 《Advanced Science》由 Wiley‐VCH GmbH 出版。

Targeted therapy remains the future of anti-cancer drug development, owing to the lack of specificity of current treatments which lead to damage in healthy normal tissues. ATR inhibitors have in recent times demonstrated promising clinical potential, and are currently being evaluated in the clinic. However, despite the considerable optimism for clinical success of these inhibitors, reports of associated normal tissues toxicities remain a concern and can compromise their utility. Here, ICT10336 is reported, a newly developed hypoxia-responsive prodrug of ATR inhibitor, AZD6738, which is hypoxia-activated and specifically releases AZD6738 only in hypoxic conditions, in vitro. This hypoxia-selective release of AZD6738 inhibited ATR activation (T1989 and S428 phosphorylation) and subsequently abrogated HIF1a-mediated adaptation of hypoxic cancers cells, thus selectively inducing cell death in 2D and 3D cancer models. Importantly, in normal tissues, ICT10336 is demonstrated to be metabolically stable and less toxic to normal cells than its active parent agent, AZD6738. In addition, ICT10336 exhibited a superior and efficient multicellular penetration ability in 3D tumor models, and selectively eradicated cells at the hypoxic core compared to AZD6738. In summary, the preclinical data demonstrate a new strategy of tumor-targeted delivery of ATR inhibitors with significant potential of enhancing the therapeutic index.© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.